Congenital CMV Library of Abstracts

Pereira, L., S. Stagno, et al. (1983). "Cytomegalovirus-infected cell polypeptides immune-precipitated by sera from children with congenital and perinatal infections." Infect Immun 39(1): 100-8.

Congenital or perinatally acquired human cytomegalovirus (CMV) infections in children may be symptomatic or asymptomatic. In this study, we characterized the electrophoretic properties of CMV-infected cell polypeptides immune-precipitated by sera from children with different types of CMV infections from birth to 4 years of age. Sodium dodecyl sulfate-polyacrylamide gel analysis of immune precipitates formed with radiolabeled extracts of cells infected with CMV strain AD169 showed the following. (i) Electrophoretic profiles of CMV polypeptides immune-precipitated by sera from children with perinatal and congenital infections were similar. At least 11 polypeptides with apparent molecular weights of 150,000, 140,000, 110,000, 100,000, 74,000, 66,000, 50,000, 49,000, 34,000, 25,000, and 20,000 were precipitated. Antibody titer in anticomplement immunofluorescence tests and virus titer in urine correlated with the intensity of polypeptide profiles in autoradiograms. (ii) The initial immune response of children with symptomatic congenital infections was delayed as compared to that of children with asymptomatic congenital and perinatal CMV infections. Sera obtained serially from symptomatic children for years after birth continued to precipitate CMV polypeptides, whereas sera from children with subclinical congenital infections precipitated lesser amounts over time. (iii) Immune precipitates obtained with sera from CMV-infected patients and with monoclonal antibodies to CMV contained polypeptides with comparable electrophoretic and immunological properties.

Mostoufi-Zadeh, M., S. G. Driscoll, et al. (1984). "Placental evidence of cytomegalovirus infection of the fetus and neonate." Arch. Pathol. Lab. Med. 108(5): 403-406.

Nine cases of congenital cytomegalovirus infection were diagnosed at Brigham and Women's Hospital in Boston from September 1977 through July 1982. The majority of infected fetuses and newborn infants had intrauterine growth retardation, congenital malformations, microcephaly, or hydrops fetalis. In four cases, cytomegalovirus was recovered from placentas. Eight placentas were examined morphologically. Varying degrees of chronic villitis were noted in all. The most frequent lesion, found in six cases, was focal villous inflammation with mononuclear cell infiltrates. Lymphocytes predominated in this reaction. In three cases, however, the villi were also intensely infiltrated by plasma cells. Typical cytomegalic inclusion bodies were noted in these three placentas. The fetus and infants in whose placentas the plasmacytic villitis and inclusion bodies were discovered displayed the most severe manifestations of cytomegalovirus infection.

Chandler, S. H., E. R. Alexander, et al. (1985). "Epidemiology of cytomegaloviral infection in a heterogeneous population of pregnant women." J Infect Dis 152(2): 249-56.

Cervical cultures for cytomegalovirus (CMV) and samples of blood for antibody to CMV were obtained from 1,129 pregnant women: 57% of the women had antibody to CMV, and 14% of seropositive women shed virus. Logistic regression analysis showed that seropositivity correlated with lower socioeconomic status, birth outside North America, multigravidity, older age, history of abnormal cervical cytology, infection with Trichomonas vaginalis, a first pregnancy at less than or equal to 15 years of age, and greater total numbers of sex partners. Thus, past exposure to CMV relates both to sociocultural factors and to sexual behavior. Absence of such risk factors identifies women who are at highest risk for primary infection with CMV during pregnancy. Culture positivity in seropositive women was independently associated with younger age, later stages of pregnancy, and race. Among seropositive women less than or equal to 21 years of age, 35% shed CMV in the third trimester, a finding of epidemiological importance with regard to perinatal transmission.

Stagno, S., R. F. Pass, et al. (1986). "Primary cytomegalovirus infection in pregnancy. Incidence, transmission to fetus, and clinical outcome." JAMA 256(14): 1904-1908.

We studied 16 218 pregnant women from two income groups to determine the incidence of primary cytomegalovirus (CMV) infection and its consequences for the offspring. In the high-income group, 64.5% of the women were seronegative for CMV and 1.6% had primary CMV infection. In the low-income group, only 23.4% of the women were seronegative for CMV, but 3.7% experienced a primary infection. The rate of transmission in utero was similar in the two groups (39% and 31%). Congenital infections were more frequent in the low-income group; however, primary CMV accounted for 25% of the congenital infections in this group, in contrast to 63% of the high-income cases. Infections acquired early and late in gestation had similar rates of transmission in utero, but three infants (8%) with symptomatic congenital infection and five infants (13.5%) who have developed significant handicaps were exposed in the first half of pregnancy. Primary CMV infection during pregnancy poses a 30% to 40% risk of intrauterine transmission and adverse outcome is more likely when infection occurs within the first half of gestation.

Pass, R. F., E. A. Little, et al. (1987). "Young children as a probable source of maternal and congenital cytomegalovirus infection." N. Engl. J. Med. 316(22): 1366-70.

To identify possible sources of cytomegalovirus infection in pregnant women, we studied seven families with a recent case of congenital or maternal cytomegalovirus infection and a history of maternal contact with a young child shedding the virus. We used restriction-endonuclease techniques to compare the DNA of viral isolates collected from family members. Five families contained an infant who had congenital or perinatal infection, a mother who had had evidence of primary infection during her most recent pregnancy, and a child less than three years of age who was excreting cytomegalovirus. All five of the young children attended day-care centers at least part-time. In each of these five families, strains from family members were identical, and it is most likely that the toddler-aged child was the source of the virus for both the mother and the fetus or infant. In two other families, acquisition of cytomegalovirus by children in a day-care center was followed by seroconversion in the mother along with excretion of a strain of the virus identical to that in her child, as demonstrated by restriction- endonuclease analysis. Five of the seven fathers were tested for antibody to cytomegalovirus; four were seronegative, ruling them out as a source of infection in the mothers. These results not only strengthen evidence for the transmission of cytomegalovirus from child to mother but also indicate that infections acquired by a mother from a child can be transmitted to her fetus.

Demmler, G. J., G. J. Buffone, et al. (1988). "Detection of cytomegalovirus in urine from newborns by using polymerase chain reaction DNA amplification." J Infect Dis 158(6): 1177-1184.

Polymerase chain reaction (PCR) amplification was used to detect cytomegalovirus (CMV) in tissue culture and in urine specimens from newborns. Synthetic oligonucleotide primer pairs were used to amplify DNA from the major immediate-early and the late antigen genes of CMV. Amplified products were detected by gel electrophoresis and by dot-blot hybridization with oligonucleotide probes. Using one or both of the primer pairs and associated probes, we found 46 different tissue culture isolates of CMV that were positive; no reaction products were detected when the same primers and probes were used to amplify other herpes family viruses or human genomic DNA. Urine samples from 44 congenitally infected infants were positive when tested with one or both primer pairs and probes. When compared with tissue culture, detection by gel electrophoresis provided a sensitivity of 93%, a specificity of 100%, and a predictive value of a positive result of 100%. Dot-blot analysis raised the sensitivity to 100%. We conclude that PCR amplification may be a valuable tool for diagnosing congenital CMV infection.

Yow, M. D., D. W. Williamson, et al. (1988). "Epidemiologic characteristics of cytomegalovirus infection in mothers and their infants." Am J Obstet Gynecol 158(5): 1189-95.

In this longitudinal study of cytomegalovirus in 4578 pregnant women of middle/upper socioeconomic status in Houston, 52% had cytomegalovirus antibody when enrolled, and 48% were serologically susceptible. Studies were completed on 3899 mothers and their infants; 2.2% of these women experienced primary cytomegalovirus during pregnancy and 24% of those with primary infection transmitted cytomegalovirus to their infants. Of 22 cytomegalovirus-infected infants, 2 had disease at birth and 20 were asymptomatic. One symptomatic infant (primary maternal infection) has developmental delay. The other (immunocompromised mother with cytomegalovirus antibody before pregnancy) had hepatitis but has no symptoms at 1 year of age. On follow-up, 4 of 16 infants asymptomatic at birth have sequelae (hearing loss in 3, developmental delay in 1). All four were born to mothers with primary cytomegalovirus infection. Infant outcome was not related to trimester of maternal infection.

Britt, W. J. and L. G. Vugler (1990). "Antiviral antibody responses in mothers and their newborn infants with clinical and subclinical congenital cytomegalovirus infections." J Infect Dis 161(2): 214-9.

Human cytomegalovirus (HCMV)-specific antibodies were assayed in cord serum and the respective maternal serum from two groups of newborn infants with congenital HCMV infection. One group of infants exhibited clinically apparent infection with multiple organ system involvement, whereas the second group had subclinical infections. Levels of virus-specific IgG antibodies reactive with several virus-encoded proteins including those reactive with the major envelope glycoprotein complex were significantly higher in cord serum and maternal delivery serum from the group of infants with clinically apparent infection than in serum from those with subclinical infection. Maternal delivery serum from the group with subclinical infection had significantly higher levels of IgM virus-binding antibody and lower levels of IgG virus-binding antibody than did the respective serum from the group with clinically apparent infection, suggesting maternal acquisition occurred later in gestation in the group with subclinical infection. These results suggested that deficiencies in the HCMV-specific antibody response were not associated with clinically apparent congenital infection and that other factors, such as early virus acquisition during pregnancy, might contribute to the severity of intrauterine HCMV infection.

Pass, R. F., C. Hutto, et al. (1990). "Increased rate of cytomegalovirus infection among day care center workers." Pediatr Infect Dis J 9(7): 465-70.

Child care workers are potentially at risk for occupational exposure to cytomegalovirus, the leading cause of congenital infection in the United States. Preschool children often shed cytomegalovirus and commonly transmit virus to peers and parents. Workers from 32 day care centers were enrolled and tested for serum antibody to cytomegalovirus; 318 (62.5%) were seropositive. By logistic regression analysis the only variables significantly (P less than 0.05) associated with seropositivity at enrollment were older age and nonwhite race, though contact with younger children (less than 2 years of age) attained a P value of 0.06. Follow-up sera were obtained at 6-month intervals from 82 initially seronegative workers; 19 seroconverted in a median interval of 14 months, a rate of 20%/year, approximately 10-fold higher than the expected rate. The only demographic or employment variable associated with seroconversion was contact with children younger than 3 years of age for at least 20 hours per week (P = 0.03). Day care center workers have a markedly increased risk for acquisition of cytomegalovirus; those who could become pregnant should be appropriately counseled regarding prevention and consequences of cytomegalovirus infection during pregnancy.

Demmler, G. J. (1991). "Infectious Diseases Society of America and Centers for Disease Control. Summary of a workshop on surveillance for congenital cytomegalovirus disease." Rev Infect Dis 13(2): 315-29.

Each year in the United States, 30,000 to 40,000 infants are born congenitally infected with cytomegalovirus (CMV), and more than 9,000 of these children suffer permanent sequelae. The purpose of this workshop was to present and discuss current information on the epidemiology, diagnosis, treatment, and prevention of CMV disease in mothers and their infants. The participants concluded that congenital CMV disease is a significant public health problem that, to date, has been largely ignored. They also agreed that certain child-rearing practices, such as the common use of day-care centers and breast-feeding, have changed the epidemiology of CMV in the United States and that the next decade may bring an increase in congenital CMV disease in certain groups. Therefore, a national system for surveillance of congenital CMV disease was established; its goals are to characterize trends over time, to identify risk groups, and to lay the groundwork for evaluation of future intervention programs. In addition, the surveillance system will be used to educate the medical and lay communities about congenital CMV disease and to facilitate collaborative efforts in research.

Fowler, K. B. and R. F. Pass (1991). "Sexually transmitted diseases in mothers of neonates with congenital cytomegalovirus infection." J. Infect. Dis. 164(2): 259-64.

To identify maternal risk factors for intrauterine transmission of cytomegalovirus (CMV), a case-control study of 175 mothers of neonates with congenital CMV infection was undertaken. Cases and 358 randomly selected controls delivered neonates between 1980 and 1988; in this interval neonates were routinely tested for viruria. Eighty-four percent of the study population was black and greater than 87% received prenatal care. Women with gonorrhea, trichomoniasis, or bacterial vaginosis had an increased risk of intrauterine transmission of CMV, as did those who were primigravid (odds ratios, 1.8-2.5). Women who were young, unmarried, and of lower income were almost four times more likely to deliver a CMV-infected newborn than were those who did not have all three of these factors. These results in a predominantly black, low-income population indicate a greater risk for congenital CMV infection in offspring of young, single, primigravid mothers. The association with gonorrhea and other sexually transmitted infections suggests that sexual activity is an important source of maternal CMV infections that result in congenital infection in this population.

Boppana, S. B., R. F. Pass, et al. (1992). "Symptomatic congenital cytomegalovirus infection: neonatal morbidity and mortality." Pediatr Infect Dis J 11(2): 93-99.

Knowledge of the natural history of symptomatic congenital cytomegalovirus (CMV) infection in the newborn is essential in order to anticipate complications and assess the potential benefit from antiviral therapy. To define the disease course we reviewed data on 106 neonates with symptomatic congenital CMV infection diagnosed and managed by the investigators. Petechiae, jaundice and hepatosplenomegaly were each noted in 70% or more patients. Microcephaly was noted in 54 of 102 (53%) at birth. Elevated alanine aminotransferase, conjugated hyperbilirubinemia and thrombocytopenia were seen in 83, 81 and 77%, respectively. Eighty-six percent had at least two of the manifestations highly suggestive of congenital infection. Platelet count fell to its nadir during the second week of life whereas elevated alanine aminotransferase and direct bilirubin persisted past the first month. In spite of the difficulty in assessing central nervous system function in the newborn, evidence of damage was present in the majority. Seventy-two had microcephaly, poor suck, lethargy/hypotonia or seizures. Abnormal computerized tomographic scan was present in 16 of 20 (80%) and decreased hearing in 20 of 39 (56%). Cerebrospinal fluid protein was greater than 120 mg/dl in 24 of 52 (46%) and this elevation was associated with neurologic abnormalities as well as hearing loss. The mean length of hospital stay was 13 and 22.4 days for term and preterm infants, relatively. Thirteen infants (12%) died during the first 6 weeks of life. Disseminated CMV infection with multiorgan involvement was evident in 7 of 9 at postmortem examination. We conclude that neonates with symptomatic congenital CMV infection have a multi-system disease with significant morbidity and mortality.

Fowler, K. B., S. Stagno, et al. (1992). "The outcome of congenital cytomegalovirus infection in relation to maternal antibody status." N. Engl. J. Med. 326(10): 663-667.

BACKGROUND. Intrauterine transmission of cytomegalovirus (CMV) can occur whether a mother has prior immunity or acquires CMV for the first time during pregnancy. The degree of protection afforded an infected infant by the presence of antibody in the mother before conception is uncertain. METHODS. We compared the outcomes of CMV-infected infants born to mothers who acquired primary CMV infection during pregnancy (primary-infection group) with those of CMV-infected infants born to mothers with immunity (recurrent-infection group). Screening for viruria identified 197 newborns with congenital CMV infection. Stored serum samples were used to categorize maternal infection as either primary or recurrent. We followed 125 infants from the primary- infection group and 64 from the recurrent-infection group. Serial medical, audiologic, psychometric, and eye examinations were used to identify sequelae of CMV infection. RESULTS. Only infants in the primary-infection group had symptomatic CMV infection at birth (18 percent). After a mean follow-up of 4.7 years, one or more sequelae were seen in 25 percent of the primary-infection group and in 8 percent of the recurrent-infection group. Thirteen percent of infants whose mothers had primary infection during pregnancy had mental impairment (IQ less than or equal to 70), as compared with none of those whose mothers had recurrent CMV infections. Sensorineural hearing loss was found in 15 percent of those in the primary-infection group and in only 5 percent of those in the recurrent-infection group. Bilateral hearing loss was identified only among children in the primary-infection group (8 percent). CONCLUSIONS. The presence of maternal antibody to CMV before conception provides substantial protection against damaging congenital CMV infection in the newborn. Primary maternal infection during pregnancy is associated with more severe sequelae of congenital CMV infection.

Muhlemann, K., R. K. Miller, et al. (1992). "Cytomegalovirus infection of the human placenta: an immunocytochemical study." Human Pathology 23(11): 1234-1237.

In congenital cytomegalovirus (CMV) infection histologic evaluation of the placenta is often unrevealing. In the present study immunocytochemistry to CMV immediate early and early nuclear antigens was used to characterize placental involvement in six cases of symptomatic intrauterine CMV infection. Histologic examination had demonstrated diagnostic viral inclusions in one placenta and non-specific villitis in another. However, immunocytochemistry revealed CMV infection in five of the six placentas, including three with no pathologic changes on routine histologic evaluation. Infected cells were located primarily in the villous stroma. In one case immunoperoxidase staining showed infection in the syncytiotrophoblast. Infected endothelial cells were demonstrated by double staining for CMV and factor VIII antigen. No double-stained cells were seen in tissue sections stained for CMV immediate early nuclear antigen or the human macrophage-associated CD68 antigen, which is expressed in Hofbauer cells. In conclusion, specific immunoperoxidase staining was more sensitive for demonstrating placental CMV infection than was histologic examination and it aided in the characterization of infected cells.

Boppana, S. B., R. F. Pass, et al. (1993). "Virus-specific antibody responses in mothers and their newborn infants with asymptomatic congenital cytomegalovirus infections." J Infect Dis 167(1): 72-7.

Human cytomegalovirus (HCMV)-specific antibody response was analyzed to determine its relationship with sequelae in children with asymptomatic congenital HCMV infection. IgG antibodies reactive with envelope glycoprotein gB were significantly higher in cord and maternal delivery serum of infants developing hearing loss than in those without any sequelae. Women of hearing impaired children had higher levels of serum anti-gB IgG and HCMV IgM at first prenatal visit (8-16 weeks gestation) than did those with children with normal hearing. Kinetics of the antibody response revealed that women with hearing impaired children had peak anti-gB and IgM response at the first prenatal visit compared with at or near delivery in mothers of normal children. These results suggested that women who delivered infants developing hearing loss had a more intense and prolonged antibody response, and factors such as early virus acquisition during pregnancy might contribute to the development of sequelae in asymptomatic congenital HCMV infection.

Fowler, K. B., S. Stagno, et al. (1993). "Maternal age and congenital cytomegalovirus infection: screening of two diverse newborn populations, 1980-1990." J Infect Dis 168(3): 552-6.

Cytomegalovirus (CMV) is the leading cause of congenital viral infection in the United States. To prevent damaging congenital CMV infections, it is necessary to have accurate population estimates of prevalence and to identify maternal factors associated with an elevated risk of congenital infection in the newborn. From 1980 through 1990, 17,163 offspring of predominantly low-income nonwhite women who delivered at a public hospital and 9892 newborns of predominantly mid- to upper-income white women who delivered at a private hospital were screened for congenital CMV infection. Women 20 years old (adjusted prevalence odds ratio [POR], 4.8; 95% confidence interval [CI], 2.6- 8.9) at the public hospital and all nonwhite women (adjusted POR, 1.6; 95% CI, 1.1-2.2) had an increased risk of delivering an infected newborn. Newborns of adolescent women in both populations had the highest prevalence of clinically apparent infection. Offspring of nonwhite low-income adolescents are at greatest risk for congenital CMV infection and more damaging sequelae.

Hicks, T., K. Fowler, et al. (1993). "Congenital cytomegalovirus infection and neonatal auditory screening." J Pediatr 123(5): 779-782.

Auditory screening of newborn infants has been recommended on the basis of the presence of risk criteria, including congenital infection. We assessed the ability of risk criteria-based neonatal auditory brain stem response to identify infants with hearing loss resulting from congenital cytomegalovirus (CMV) infection. Data from 6 1/2 years of risk criteria-based neonatal auditory screening were compared with the results of screening of all newborn infants for congenital CMV infection. Infants with congenital CMV infection received follow-up hearing evaluations. Congenital CMV infection was found in 167 (1.3%) of 12,371 infants; 134 had follow-up hearing evaluations, and 14 (10.4%) had confirmed sensorineural hearing loss. The rate of sensorineural hearing loss resulting from congenital CMV infection was 14 per 12,371 infants, of 1.1 per 1000 live births; the rate of bilateral loss > or = 50 dB was 0.6 per 1000. Although 2036 infants received auditory screening because of risk criteria, only 34 (20%) of 167 infants with congenital CMV infection were included. Only 2 (14%) of 14 children with sensorineural hearing loss caused by CMV were identified by risk criteria-based screening. We conclude that congenital CMV infection is an important cause of hearing impairment. Neonatal auditory screening based on the presence of risk criteria will fail to identify the majority of cases of sensorineural hearing loss caused by congenital CMV infection.

Demmler, G. J. (1994). "Congenital cytomegalovirus infection." Semin Pediatr Neurol 1(1): 36-42.

Congenital cytomegalovirus (CMV) infection is the most common congenital infection in humans, infecting 30,000 to 40,000 newborns each year in the United States and leaving more than 9,000 of these children with permanent neurological sequelae. Recognition of the importance of this public health problem has been growing, and recent advances in surveillance, early detection, treatment and even prevention are presented in this review.

Harrison, C. J., W. J. Britt, et al. (1995). "Reduced congenital cytomegalovirus (CMV) infection after maternal immunization with a guinea pig CMV glycoprotein before gestational primary CMV infection in the guinea pig model." J Infect Dis 172(5): 1212-20.

This study evaluated the effects of subunit guinea pig (GP) cytomegalovirus (CMV) immunization on congenital infection. Two 25-micrograms doses of an abundant GPCMV glycoprotein, the gp60-90 complex, plus adjuvant to GPs before pregnancy produced virus-specific humoral (neutralizing and ELISA) and cellular (proliferative and delayed type hypersensitivity) responses. Viral challenge before midgestation resulted in shorter maternal viremia in immunized than in unimmunized dams (3 vs. 17 days). Litters of immunized dams had reduced organ involvement and rates of congenital infection (48% vs. 18%) and increased mean birth weights (74 vs. 99 g). Amplification of DNA extracted from pup blood or organs with primers from the gB gene of GPCMV revealed congenital infection in some pups without detectable CMV by classic culture techniques. These data suggest that induction of preconception immunity to CMV by vaccine could be useful in reducing both the incidence and severity of congenital CMV disease.

Istas, A. S., G. J. Demmler, et al. (1995). "Surveillance for congenital cytomegalovirus disease: a report from the National Congenital Cytomegalovirus Disease Registry." Clin Infect Dis 20(3): 665-70.

A national surveillance program for congenital cytomegalovirus (CMV) disease was initiated in 1990. In 4 years 285 cases were reported without seasonal patterns. Mean birth statistics were as follows: gestational age, 36 weeks; weight, 2,224 g; length, 45 cm; and head circumference, 30 cm. Of the infants 68% had CNS involvement, which was significantly (P < .005) associated with a direct bilirubin level of > or = 3 mg/dL, petechiae, an alanine aminotransferase level of > 100 U/L, a platelet count of < or = 75,000/mm3, hepatomegaly, and splenomegaly (P < .05). Maternal demographics revealed that the mean age was 23 years (range, 13-38 years), 59% were white, 33% were black, 47% had low incomes (receiving Medicaid), and 45% were primiparous. Compared with 1990 birth statistics in the United States, mothers of infants with congenital CMV disease were younger, and a greater percentage of these mothers were black. Two distinct maternal groups were identified on the basis of age, socioeconomic status, and parity. This finding may reflect different modes of transmission and suggest target populations for future CMV vaccine initiatives.

Jauniaux, E., D. Jurkovic, et al. (1995). "Materno-fetal immunoglobulin transfer and passive immunity during the first trimester of human pregnancy." Hum Reprod 10(12): 3297-300.

Passive transfer of immunity from the mother to the first trimester fetus is of particular interest because of the reported high incidence of serious fetal sequelae due to congenital infection. We have examined the relationship between maternal serum, coelomic fluid and amniotic fluid concentrations of immunoglobulin (Ig) and complement. Ig fractions G (IgG), A (IgA), and M (IgM) and complement factors 3 (C3) and 4 (C4) were measured in 34 normal pregnancies between 6 and 12 weeks of gestation. The concentrations of specific antibodies for Toxoplasma gondii, cytomegalovirus (CMV) and rubella were also measured on 21 matched samples from the same study group. IgG and IgA concentrations were detected in all coelomic fluid samples whereas IgG was only measurable in two amniotic fluid samples. IgG and IgA concentrations were respectively 28 and 128 times lower in coelomic fluid than in maternal serum and probably reflect fetal serum concentrations. Significant positive linear correlations were found between gestational age and the coelomic concentrations of IgG (P = 0.001) and IgA (P = 0.014). There was no obvious association between immunoglobulin concentrations in coelomic fluid and maternal serum suggesting increasing active transport across the placenta with advancing gestation. IgM, C3 and C4 were not detected in coelomic or amniotic fluid samples. Specific antibodies were found in 13 out of 63 samples of coelomic fluid and in 32 out of 63 samples of maternal serum. They were found in coelomic fluid only if they were present in maternal serum. These results suggest that maternal IgG and IgA are potentially available to the embryo as early as the 6th week of gestation. The presence in the coelomic fluid of the IgG fraction, both total and infectious agent-specific transferred via the placenta, indicates that they may provide limited protection against congenital infection in the first trimester.

"Nelson, C. T., A. S. Istas, et al. (1995). "PCR detection of cytomegalovirus DNA in serum as a diagnostic test for congenital cytomegalovirus infection." J Clin Microbiol 33(12): 3317-8.

PCR detected cytomegalovirus (CMV) DNA in the serum of 18 of 18 infants with symptomatic congenital CMV infection, 1 of 2 infants with asymptomatic congenital CMV infection, and 0 of 32 controls. Serum CMV PCR provided a rapid, sensitive, and specific method for diagnosis of congenital CMV infection in infants who were symptomatic at birth.

"Revello, M. G., F. Baldanti, et al. (1995). "Polymerase chain reaction for prenatal diagnosis of congenital human cytomegalovirus infection." J Med Virol 47(4): 462-6.

The reliability of the polymerase chain reaction (PCR) for prenatal diagnosis of human cytomegalovirus (HCMV) infection was determined by retrospective testing of 35 amniotic fluids identified previously as positive or negative for HCMV by virus isolation. Amniocentesis was performed in 26 pregnant women with primary HCMV infection at 14-36 weeks gestation, 3-21 weeks after maternal infection. Blood samples were obtained from 20 fetuses for IgM determination and/or virus isolation. Amniotic fluid culture led to antenatal diagnosis of HCMV in 9 of the 13 infected fetuses (sensitivity 69.2%) with one case diagnosed at a second sampling. PCR was able to detect one additional infected fetus (10/13, sensitivity 76.9%). Nested PCR did not increase sensitivity of prenatal diagnosis. Three cases were not diagnosed by all the techniques employed. The specificity of virus isolation from and DNA detection by PCR in amniotic fluid was 100%. The negative predictive value for virus isolation from amniotic fluid was 76.5% and for DNA detection by PCR 81.2%, whereas the positive predictive value was 100% for both techniques. The results showed that neither approach can detect all cases of congenital HCMV infection prenatally, and that the time interval between maternal infection and sampling seems to be a major factor affecting the reliability of prenatal diagnosis.

Adler, S. P. (1996). "Current prospects for immunization against cytomegaloviral disease." Infect Agents Dis 5(1): 29-35.

Cytomegaloviral (CMV) seronegative women who acquire a primary CMV infection during pregnancy are at the greatest risk for delivering infants who may be deaf or intellectually handicapped because of congenital CMV infection. Maternal immunization before pregnancy may protect newborns from congenital disease because mothers who are naturally seropositive are protected against secondary infection and because newborns who acquire CMV either via transfusion or transplacentally are protected if their mothers had antibodies to CMV prior to pregnancy. Further evidence for the feasibility of immunization for CMV comes from studies of patients immunocompromised following solid organ transplantation protection. These patients are protected against severe cytomegaloviral disease by immunity acquired either by wild-type infection prior to transplantation or by passive or active immunization. In three randomized placebo-controlled studies, live attenuated CMV Towne vaccine has successfully protected seronegative recipients of seropositive kidneys from severe CMV disease by inducing humoral and cellular immunity. Subunit vaccines comprised of glycoprotein gB, the viral component containing the majority of viral neutralizing epitopes, are in the early phases of study, as are studies with highly immunogenic preparations of Towne vaccine. Given all of these facts, safe and effective CMV immunoprophylaxis against CMV disease is possible.

Anderson, K. S., C. S. Amos, et al. (1996). "Ocular abnormalities in congenital cytomegalovirus infection." J Am Optom Assoc 67(5): 273-8.

BACKGROUND: Congenital cytomegalovirus (CMV) infection often results in damage to the brain, auditory system and visual system that leads to debility. This report describes the frequency, severity and effect on vision function of ocular abnormalities in a large cohort of children with congenital CMV infection. METHODS: Serial eye examinations were performed on 445 infants and children with congenital CMV infection from one month to 9 years of age, assessing anatomic integrity, motor sensory function, retina and posterior pole. RESULTS: Ocular disease was manifest principally by chorioretinitis, optic atrophy, pigmentary retinopathy and strabismus; each of these findings occurred more frequently (p < 0.05) among children who were symptomatic at birth than among those who were initially asymptomatic. These same findings were also more common among patients born after a primary maternal infection than among those born after a recurrent maternal infection. More than half of the patients with symptomatic congenital CMV infection with chorioretinitis or optic atrophy had significant binocular vision impairment. CONCLUSIONS: Ocular disease is an important sequela of congenital CMV infection that can lead to impaired vision. In order to allow for early intervention, patients with congenital CMV infection should have eye examinations beginning in early infancy.

Cha, T. A., E. Tom, et al. (1996). "Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains." J Virol 70(1): 78-83.

Nucleotide sequence comparisons were performed on a highly heterogeneous region of three human cytomegalovirus strains, Toledo, Towne, and AD169. The low-passage, virulent Toledo genome contained a DNA segment of approximately 13 kbp that was not found in the Towne genome and a segment of approximately 15 kbp that was not found in the AD169 genome. The Towne strain contained approximately 4.7 kbp of DNA that was absent from the AD169 genome, and only about half of this segment was present, arranged in an inverted orientation, in the Toledo genome. These additional sequences were located at the unique long (UL)/b' (IRL) boundary within the L component of the viral genome. A region representing nucleotides 175082 to 178221 of the AD169 genome was conserved in all three strains; however, substantial reduction in the size of the adjacent b' sequence was found. The additional DNA segment within the Toledo genome contained 19 open reading frames not present in the AD169 genome. The additional DNA segment within the Towne genome contained four new open reading frames, only one of which shared homology with the Toledo genome. This comparison was extended to five additional clinical isolates, and the additional Toledo sequence was conserved in all. These findings reveal a dramatic level of genome sequence complexity that may explain the differences that these strains exhibit in virulence and tissue tropism. Although the additional sequences have not altered the predicted size of the viral genome (230 to 235 kbp), a total of 22 new open reading frames (denoted UL133 to UL154), many of which have sequence characteristics of glycoproteins, are now defined as cytomegalovirus specific. Our work suggests that wild-type virus carries more than 220 genes, some of which are lost by large-scale deletion and rearrangement of the UL/b' region during laboratory passage.

"Demmler, G. J. (1996). "Congenital cytomegalovirus infection and disease." Advances in Pediatric Infectious Diseases 11(2): 135-62.

Pass, R. F. (1996). "Immunization strategy for prevention of congenital cytomegalovirus infection." Infectious Agents and Disease 5(4): 240-4.

Women of childbearing age are a logical target for a vaccine aimed at prevention of congenital cytomegalovirus (CMV) infections. However, the impact of a CMV vaccine could likely be enhanced by considering the sources of maternal infection and characteristics of mothers of infected newborns. Contact with preschool-age children and sexual activity are important sources of CMV infection for young women. Approximately half of infants with congenital CMV infection in the U.S. are born to unmarried, adolescent mothers. To prevent CMV infection in those who are the sources of maternal infection as well as in young, unmarried mothers, universal immunization of toddlers and preteen children should be considered.

Nelson, C. T. and G. J. Demmler (1997). "Cytomegalovirus infection in the pregnant mother, fetus, and newborn infant." Clin Perinatol 24(1): 151-60.

Cytomegalovirus (CMV) is a common virus that infects persons of all ages, races, and backgrounds. Originally described as a rare cause of "cytomegalic inclusion disease," CMV is now known to cause a broad spectrum of illness in the fetus and newborn, with most infections being asymptomatic at birth. This article discusses the epidemiology and diagnosis of CMV infection in pregnant women, the fetus, and the newborn, including recent advances in antenatal diagnosis. In addition, the challenges of treatment and prevention of congenital CMV are explored.

Ozono, K., S. Mushiake, et al. (1997). "Diagnosis of congenital cytomegalovirus infection by examination of placenta: application of polymerase chain reaction and in situ hybridization." Pediatric Pathology and Laboratory Medicine 17(2): 249-58.

We examined the placentas of 12 patients in whom congenital cytomegalovirus (CMV) infection was suspected from serological and/or pathological evaluation. Seven patients died (including four intrauterine deaths) and five survived. On histological examination, the characteristic inclusion bodies were detected in only three placentas, and villitis with plasma cell infiltration was seen in eight placentas. Immunohistochemistry using a specific antibody against CMV improved the sensitivity of CMV deletion (10 cases were positive). With the polymerase chain reaction (PCR) following the extraction of DNA from formaldehyde-fixed placenta samples, CMV DNA was detected in seven cases. All 12 subjects were diagnosed with CMV infection by additional Southern blot analysis after the PCR. CMV DNA was also detected by an in situ hybridization method in all cases. With current molecular biological techniques the placenta can be reliably used for the diagnosis of congenital CMV infection.

Soderberg-Naucler, C., K. N. Fish, et al. (1997). "Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors." Cell 91(1): 119-126.

Reactivation of human cytomegalovirus (HCMV) results in severe disease in AIDS patients and immunocompromised patients receiving blood transfusions or organ or bone marrow grafts. Although the site of HCMV latency is unknown, blood cells have been implicated as a viral reservoir. In this study, we demonstrate HCMV reactivation in vitro from seven consecutive healthy donors through allogeneic stimulation of peripheral blood mononuclear cells (PBMCs). HCMV replication was detected at 17 days poststimulation, and virus was recovered after long- term culture from a macrophage expressing dendritic cell markers. Thus, these observations demonstrate that PBMCs harbor latent HCMV, which reactivates in a myeloid lineage cell upon allogeneic stimulation.

Whitley, R. J., G. Cloud, et al. (1997). "Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase II study. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group." J Infect Dis 175(5): 1080-6.

Congenital cytomegalovirus (CMV) infection occurs in approximately 1% of newborns in the United States. A phase II evaluation was done of ganciclovir for the treatment of symptomatic congenital CMV infection. Daily doses of 8 or 12 mg/kg were administered in divided doses at 12-h intervals for 6 weeks. Clinical and laboratory evaluations sought evidence of toxicity, quantitative virologic responses in urine, plasma drug concentrations, and clinical outcome. A total of 14 and 28 babies received 8 and 12 mg/kg/day, respectively. Five additional babies received ganciclovir on a compassionate plea basis. Significant laboratory abnormalities included thrombocytopenia ( or = 50,000/mm3) in 37 babies and absolute neutropenia ( or = 500 mm3) in 29 babies. Quantitative excretion of CMV in the urine decreased; however, after cessation of therapy, viruria returned to near pretreatment levels. Hearing improvement or stabilization occurred in 5 (16%) of 30 babies at 6 months or later, indicating efficacy.

Kashden, J., S. Frison, et al. (1998). "Intellectual assessment of children with asymptomatic congenital cytomegalovirus infection." J Dev Behav Pediatr 19(4): 254-9.

The findings of previous studies examining the neurocognitive development of children with clinically inapparent (asymptomatic) cytomegalovirus (CMV) infection have demonstrated mixed results. These studies have generally depended on small sample sizes (i.e., < 50). We examined the intellectual development of children with asymptomatic congenital CMV infection using a sample larger than previous studies. Two hundred and four cases aged 5 to 200 months were compared with 177 uninfected siblings ranging in age from 6 to 203 months. Parents were administered the Developmental Profile, a measure of developmental achievement. Children who were older than 30 months were administered an objective intelligence measure. Results of this study showed that children with asymptomatic congenital CMV infection do not demonstrate intellectual impairment, and that they perform similarly to uninfected siblings. Parents tended to overestimate their child's level of functioning regardless of whether the child had CMV infection.

Morita, M., T. Morishima, et al. (1998). "Clinical survey of congenital cytomegalovirus infection in Japan." Acta Paediatr Jpn 40(5): 432-6.

BACKGROUND: The clinical features of congenital cytomegalovirus (CMV) infection in countries with a higher percentage of maternal seropositivity for CMV has rarely been reported. We conducted a national survey for the first time in Japan to investigate the prevalence of congenital CMV infection. METHODS: Questionnaires were sent in 1994 to pediatricians and obstetricians of 3398 hospitals with either more than 100 beds or a neonatal intensive care unit (NICU). The questionnaire asked for the number of new cases in 1992 and 1993, maternal status of CMV infection, diagnostic methods, clinical manifestations at birth, sequelae and prognosis. RESULTS: A total of 46 cases of CMV infection were reported for the years 1992 and 1993 by 1448 hospitals; of these 39 were symptomatic. The annual incidence of symptomatic disease was 1.6 cases/100,000 live births. Major clinical manifestations such as low birthweight, hepatosplenomegaly, petechiae and intracranial calcification were noted at birth in 38-50% of symptomatic neonates. Sequelae, such as hearing loss, mental retardation and motor disability developed in 71% of survivors. Thirty- five percent of the 49 infected infants had either died or had severe disability. Several clinical manifestations at birth, including petechiae/thrombocytopenia, were significantly associated with severe sequelae or a poor prognosis. CONCLUSION: The lower frequency of clinical findings at birth may be attributed to the higher seroprevalence of pregnant women in Japan than in Europe and the United States.

Fowler, K. B., A. J. Dahle, et al. (1999). "Newborn hearing screening: will children with hearing loss caused by congenital cytomegalovirus infection be missed?" J Pediatr 135(1): 60-64.

OBJECTIVE: To predict whether universal newborn auditory screening will identify most infants with sensorineural hearing loss (SNHL) caused by congenital cytomegalovirus (CMV) infection. STUDY DESIGN: A cohort of 388 children born between 1980 and 1996 at one hospital and identified during the newborn period as having congenital CMV infection received repeated hearing evaluations to assess whether hearing loss had occurred. RESULTS: SNHL was detected in 5.2% of all infants at birth. Late-onset SNHL occurred among the children throughout the first 6 years of life. By the age of 72 months, the cumulative incidence of SNHL was 15.4% in the cohort. Children with clinically apparent disease at birth had significantly more SNHL than children without any apparent disease (22.8% vs 4.0% at 3 months and 36.4% vs 11.3% at 72 months of age). CONCLUSIONS: Universal screening of hearing in neonates will detect less than half of all SNHL caused by congenital CMV infection. Because most infants with congenital CMV infection are without symptoms at birth, these children are unlikely to be recognized as being at risk for SNHL and will not receive further hearing evaluations to detect late-onset hearing loss. A combined approach of universal screening of neonates for hearing, as well as for detection of congenital CMV infection, needs to be considered.

Nigro, G., M. Mazzocco, et al. (1999). "Prenatal diagnosis of fetal cytomegalovirus infection after primary or recurrent maternal infection." Obstet Gynecol 94(6): 909-14.

OBJECTIVE: To determine the reliability of prenatal diagnosis of cytomegalovirus infection in women with primary or recurrent infection. METHODS: Amniotic fluid (AF) samples from 117 pregnant women were evaluated for cytomegalovirus culture and cytomegalovirus-DNA detection. Neonatal and postnatal samples also were examined to confirm or exclude transmission of maternal-fetal cytomegalovirus infection. RESULTS: Of 25 women with primary cytomegalovirus infection, 13 (52%) had cytomegalovirus-positive AF samples by polymerase chain reaction (PCR), nine of which also were diagnosed by culture. All eight neonates born to mothers whose AF was cytomegalovirus-positive by PCR and culture were cytomegalovirus infected, and three were symptomatic. One aborted fetus had cytomegalovirus-DNAemia. Of four women with cytomegalovirus-positive AF samples by PCR only, two delivered asymptomatic cytomegalovirus-infected neonates and two aborted (one fetus had cytomegalovirus encephalopathy). Of 45 mothers with recurrent infection, two with AF cytomegalovirus-positive by PCR and culture, and another with cytomegalovirus-positive AF samples by PCR only, aborted cytomegalovirus-DNA-positive fetuses. Of the other seven women with cytomegalovirus-positive AF samples by PCR only, two delivered asymptomatic cytomegalovirus-infected neonates, two delivered neonates cytomegalovirus-positive by PCR only (one was symptomatic), and three delivered infants cytomegalovirus-negative by PCR and culture. All 47 mothers with nonactive cytomegalovirus infection and cytomegalovirus-negative AF samples had uninfected neonates. Polymerase chain reaction was superior to viral culture in sensitivity and negative predictive value (100% compared with 57% and 94%, respectively) but was lower in specificity and positive predictive value (97% and 83%, respectively, compared with 100%). CONCLUSION: Prenatal diagnosis of fetal cytomegalovirus infection should include PCR in addition to viral culture, particularly for congenital cytomegalovirus infections following maternal recurrence.

Nishimura, N., H. Kimura, et al. (1999). "Prevalence of maternal cytomegalovirus (CMV) antibody and detection of CMV DNA in amniotic fluid." Microbiol Immunol 43(8): 781-4.

The prevalence of cytomegalovirus (CMV) IgG antibody was determined in 573 pregnant women in the first trimester. The overall prevalence of CMV IgG antibody was 77.5%. The rate of seropositivity was 67.7% in women < 25 yr, and increased with age to 85.7% in women 40 yr. These results imply that young women in Japan are at increased risk for primary CMV infection during pregnancy and that congenital CMV infection rates might increase in the future. We conducted a prospective study of 75 pregnant women who underwent amniocentesis for various indications to determine if CMV DNA could be detected in the amniotic fluid. None had symptoms associated with CMV infection, CMV IgM antibody, or seroconversion to CMV IgG antibody during pregnancy. CMV DNA was not detected in the amniotic fluid using a polymerase chain reaction assay. The 65 fetuses, including 3 sets of twins, were followed through birth. CMV DNA was not detected in urine samples obtained within the first 2 weeks of life. In conclusion, CMV DNA was not detected in the amniotic fluid of women who did not have CMV infection. These results, however, suggest that the negative predictive value of prenatal amniotic fluid analysis is high and that the presence of CMV DNA in the amniotic fluid has clinical significance for the diagnosis of congenital CMV infection if detected in pregnant women.

Revello, M. G., M. Zavattoni, et al. (1999). "Diagnostic and prognostic value of human cytomegalovirus load and IgM antibody in blood of congenitally infected newborns." J Clin Virol 14(1): 57-66.

BACKGROUND: Diagnosis of congenital human cytomegalovirus (HCMV) infection relies on virus isolation from urine collected in the first 3 weeks of life. However, very little is known about the presence, levels and duration of HCMV pp65 antigenemia, viremia and DNAemia in congenitally infected newborns. OBJECTIVES: To investigate the diagnostic and prognostic value of HCMV load determination in blood of newborns/infants with congenital HCMV infection. STUDY DESIGN: HCMV pp65 antigenemia, viremia and DNAemia were investigated in 116 sequential peripheral blood leukocytes (PBL) samples from 41 newborns/infants with congenital HCMV infection and in 34 PBL samples from 34 uninfected newborn. Virus-specific IgM were determined in parallel on 145 sequential serum samples. RESULTS: Compared to virus isolation from urine, sensitivities of DNAemia, antigenemia, viremia, and IgM determination were 100, 42.5, 28.2, and 70.7%, respectively. Specificity was 100% for all assays. Antigenemia, viremia and DNAemia levels were significantly higher and persisted longer in newborns with symptomatic infection compared to subclinically infected babies, whereas no difference was observed for virus-specific IgM antibody between the two groups. CONCLUSIONS: (i) determination of viral DNA in blood at birth appears to be a sensitive and specific marker for diagnosis of congenital HCMV infection; (ii) significantly higher levels of HCMV load were detected in infants with symptomatic HCMV infection; and (iii) virus clearance from blood occurs spontaneously both in symptomatic and subclinically infected infants. However, the process takes longer in infants presenting with symptoms at birth.

Dahle, A. J., K. B. Fowler, et al. (2000). "Longitudinal investigation of hearing disorders in children with congenital cytomegalovirus." J Am Acad Audiol 11(5): 283-90.

This investigation consisted of a longitudinal study of the effects of congenital cytomegalovirus (CMV) infection on hearing sensitivity in 860 children with documented asymptomatic or symptomatic congenital CMV infection. Of the 651 children with asymptomatic CMV infection, 48 (7.4%) developed sensorineural hearing loss (SNHL), compared to 85 (40.7%) of the children with symptomatic CMV infection. Children in both groups experienced latent effects consisting of delayed onset of loss, threshold fluctuations, and/or progressive loss of hearing. It can be concluded that congenital CMV infection is a leading cause of SNHL in children. The late onset and progression of loss necessitates continued monitoring of hearing sensitivity in this population.

Fisher, S., O. Genbacev, et al. (2000). "Human cytomegalovirus infection of placental cytotrophoblasts in vitro and in utero: implications for transmission and pathogenesis." J. Virol. 74(15): 6808-6820.

Human cytomegalovirus (CMV) is the leading cause of prenatal viral infection. Affected infants may suffer intrauterine growth retardation and serious neurologic impairment. Analysis of spontaneously aborted conceptuses shows that CMV infects the placenta before the embryo or fetus. In the human hemochorial placenta, maternal blood directly contacts syncytiotrophoblasts that cover chorionic villi and cytotrophoblasts that invade uterine vessels, suggesting possible routes for CMV transmission. To test this hypothesis, we exposed first- trimester chorionic villi and isolated cytotrophoblasts to CMV in vitro. In chorionic villi, syncytiotrophoblasts did not become infected, although clusters of underlying cytotrophoblasts expressed viral proteins. In chorionic villi that were infected with CMV in utero, syncytiotrophoblasts were often spared, whereas cytotrophoblasts and other cells of the villous core expressed viral proteins. Isolated cytotrophoblasts were also permissive for CMV replication in vitro; significantly, infection subsequently impaired the cytotrophoblasts' ability to differentiate and invade. These results suggest two possible routes of CMV transmission to the fetus: (i) across syncytiotrophoblasts with subsequent infection of the underlying cytotrophoblasts and (ii) via invasive cytotrophoblasts within the uterine wall. Furthermore, the observation that CMV infection impairs critical aspects of cytotrophoblast function offers testable hypotheses for explaining the deleterious effects of this virus on pregnancy outcome.

Guerra, B., T. Lazzarotto, et al. (2000). "Prenatal diagnosis of symptomatic congenital cytomegalovirus infection." Am J Obstet Gynecol 183(2): 476-82.

OBJECTIVE: The aim of this study was to evaluate whether the amniotic viral load of mothers with primary cytomegalovirus infection correlate with fetal or neonatal outcomes. STUDY DESIGN: Sixty-eight of 138 pregnant women with primary infection defined by immunoglobulin G seroconversion or the presence of immunoglobulin M with low immunoglobulin G avidity accepted amniocentesis. Polymerase chain reaction and quantitative polymerase chain reaction were used to detect amniotic fluid cytomegalovirus. Cytomegalovirus infection in neonates was determined by means of urinary viral isolation during the first week after birth or the histologic examination of tissue from aborted fetuses. RESULTS: Cytomegalovirus infection was found in 16 fetuses and neonates (23%), 5 of whom had symptoms. Quantitative polymerase chain reaction showed that the presence of >/=10(3) genome equivalents predicted mother-child infection with 100% probability; >/=10(5) genome equivalents predicted the development of a symptomatic infection. CONCLUSION: Fewer than expected cytomegalovirus-infected fetuses are at risk for development of cytomegaloviral disease, and this fact may be useful in counseling pregnant women with primary cytomegalovirus infection.

Lazzarotto, T., S. Varani, et al. (2000). "Prenatal indicators of congenital cytomegalovirus infection." J Pediatr 137(1): 90-5.

OBJECTIVE: To assess the validity of a diagnostic protocol designed to predict the outcome of newborns of mothers suspected to have primary cytomegalovirus (CMV) infection during the first 4 months of pregnancy. STUDY DESIGN: Anti-CMV immunoglobulin (Ig) M detection by enzyme immunoassay and immunoblot together with the determination of anti-CMV IgG avidity allowed us to classify 456 women as (1) uninfected, (2) undergoing either a primary or a recurrent infection, or (3) having an undefined serologic condition. Prenatal diagnosis was carried out at 21 to 23 weeks' gestation for women. The presence of the virus in the amniotic fluid was determined by culture, polymerase chain reaction, and quantitative polymerase chain reaction. Macroscopic and histologic examinations were undertaken on tissue from aborted fetuses, whereas for newborns culture was performed on urine sampled during the first week of life. RESULTS: Congenital infections were found exclusively among women undergoing a primary infection. The quantitative determination of CMV DNA in the amniotic fluid of at least 10(3) genome equivalents gave a 100% certainty of detecting an infected fetus. Higher viral loads were associated with fetuses or newborns with symptoms. CONCLUSIONS: IgM tests and the IgG avidity determination can identify all women at risk of transmitting CMV. Furthermore, a high CMV DNA load in amniotic fluid could be an indicator of symptomatic congenital infection at a relatively early stage of pregnancy.

Noyola, D. E., G. J. Demmler, et al. (2000). "Cytomegalovirus urinary excretion and long term outcome in children with congenital cytomegalovirus infection. Congenital CMV Longitudinal Study Group." Pediatr Infect Dis J 19(6): 505-10.

BACKGROUND: Cytomegalovirus (CMV) is the most frequent cause of congenital infection, and both symptomatic and asymptomatic infants may have long term sequelae. Children with congenital CMV infection are chronically infected and excrete CMV in the urine for prolonged periods. However, the effect of prolonged viral replication on the long term outcome of these children is unknown. OBJECTIVE: To determine whether duration of CMV excretion is associated with outcome at 6 years of life in symptomatic and asymptomatic congenitally infected children. METHODS: Longitudinal cohort study. Children congenitally infected with CMV were identified at birth and followed prospectively in a study of long term effects of congenital CMV infection. The relationship between duration of CMV urinary excretion and growth, neurodevelopment and presence and progression of sensorineural hearing loss (SNHL) at 6 years of age was determined. RESULTS: There was no significant difference in the duration of viral urinary excretion between children born with asymptomatic (median, 4.55 years) and symptomatic (median, 2.97 years) congenital CMV infection (P = 0.11). Furthermore there was no association between long term growth or cognitive outcome and duration of viral excretion. However, a significantly greater proportion of children who excreted CMV for <4 years had SNHL and progressive SNHL compared with children with CMV excretion >4 years (P = 0.019, P = 0.009, respectively). CONCLUSIONS: Children congenitally infected with CMV are chronically infected for years, but the duration of CMV urinary excretion is not associated with abnormalities of growth, or neurodevelopmental deficits. However, SNHL and progressive SNHL were associated with a shorter duration of CMV excretion.

Bourne, N., M. R. Schleiss, et al. (2001). "Preconception immunization with a cytomegalovirus (CMV) glycoprotein vaccine improves pregnancy outcome in a guinea pig model of congenital CMV infection." J Infect Dis 183(1): 59-64.

The guinea pig (gp) model of congenital cytomegalovirus (CMV) infection was used to evaluate a gpCMV glycoprotein vaccine. Hartley guinea pigs were immunized 3 times with 50 microg of lectin column-purified glycoproteins prepared from gpCMV-infected or -uninfected tissue culture. Immunization with the gpCMV vaccine produced seroconversion in all animals. Animals then were placed with gpCMV-seronegative male animals and were challenged late in pregnancy with virulent salivary gland-passaged gpCMV. Immunization with gpCMV glycoproteins significantly improved pregnancy outcome, with 54 of 63 pups live-born in immunized animals, compared with 21 of 48 in the controls P.001).> In addition, virus was isolated from 24 of 54 live-born pups born to immunized mothers, compared with 16 of 20 live-born pups born to controls, indicating that immunization significantly reduced in utero transmission in surviving animals (P.01).

Enders, G., U. Bader, et al. (2001). "Prenatal diagnosis of congenital cytomegalovirus infection in 189 pregnancies with known outcome." Prenat Diagn 21(5): 362-77.

Prenatal diagnosis (PD) of fetal cytomegalovirus (CMV) infection was performed in 242 pregnancies, with known outcome in 189 cases. In 141/189 pregnancies, PD was carried out on account of suspicious maternal CMV serology up to gestational week (WG) 23, and in 48 cases on account of abnormal ultrasonic findings detected between WG 18 and 39. Chorionic villus samples (n = 6), amniotic fluid (AF, n = 176) and/or fetal blood specimens (n = 80) were investigated for detection of virus by cell culture, shell vial assay, PCR and/or CMV-specific IgM antibodies. Of 189 fetuses correctly evaluated by CMV detection either in fetal tissue following therapeutic abortion/stillbirth (n = 24) or in urine of neonates within the first 2 weeks of life (n = 33), 57 were congenitally infected. In women with proven or suspected primary infection, the intrauterine transmission rates were 20.6% (7/34) and 24.4% (10/41), respectively. Of the congenitally infected live-born infants, 57.6% (19/33) had symptoms of varying degree. The overall sensitivity of PD in the serologic and ultrasound risk groups was 89.5% (51/57). A sensitivity of 100% was achieved by combining detection of CMV-DNA and CMV-specific IgM in fetal blood or by combined testing of AF and fetal blood for CMV-DNA or IgM antibodies. There was no instance of intrauterine death following the invasive procedure. The predictive value of PD for fetal infection was 95.7% (132/138) for negative results and 100% (51/51) for positive results. Correct results for congenital CMV infection by testing AF samples can be expected with samples obtained after WG 21 and after a time interval of at least 6 weeks between first diagnosis of maternal infection and PD. In case of negative findings in AF or fetal blood and the absence of ultrasound abnormalities at WG 22-23, fetal infection and neonatal disease could be excluded with high confidence. Positive findings for CMV infection in AF and/or fetal blood in combination with CMV suspicious ultrasound abnormalities predicted a high risk of cytomegalic inclusion disease (CID). Furthermore, detection of specific IgM antibodies in fetal blood was significantly correlated with severe outcome for the fetus or the newborn (p = 0.0224). However, normal ultrasound of infected fetuses at WG 22-23 can neither completely exclude an abnormal ultrasound at a later WG and the birth of a severely damaged child nor the birth of neonates which are afflicted by single manifestations at birth or later and of the kind which are not detectable by currently available ultrasonographic techniques.

Gouarin, S., P. Palmer, et al. (2001). "Congenital HCMV infection: a collaborative and comparative study of virus detection in amniotic fluid by culture and by PCR." J Clin Virol 21(1): 47-55.

Cytomegalovirus (HCMV) infection is the leading cause of congenital virus infection in developed countries, affecting an estimated 1% of births. This antenatal infection can cause serious sequelae. Strategies for prevention and treatment must, therefore, be agreed upon, entailing a preliminary performance assessment of antenatal virus diagnosis techniques. Between 1992 and 1999, HCMV serology status was established for 19456 pregnant women in four French hospitals. Seronegative patients (55.4%) were given serology screening, and antenatal diagnosis was given to 152 women who had shown seroconversion during their pregnancies (1.4%). The detection of HCMV transmission from mother to fetus was finally established in 95 cases, using polymerase chain reaction (PCR) and viral culture methods for detecting HCMV in the amniotic fluid. These results were compared with viral culture of children's urine after birth, enabling us to distinguish between children really infected in utero (30%) and non-infected children (70%). The results of the virus culture and those of PCR were identical in 94 of the 95 cases, with one discrepancy (culture-/PCR+). The two diagnosis techniques had identical sensitivity (72%), with culture proving slightly more specific than PCR (98.4% as opposed to 96.9%). Positive prediction values for culture and for PCR were, respectively, 95.6 and 91.3%. Antenatal virus diagnosis on amniotic fluid was negative with both techniques in 8 out of 29 cases of children born with HCMV infection (VPN=89%). Over half of these wrongly negative results can be explained by amniocentesis carried out too early in the pregnancy or too early with respect to the mother's primary infection.

Bissinger, A. L., C. Sinzger, et al. (2002). "Human cytomegalovirus as a direct pathogen: correlation of multiorgan involvement and cell distribution with clinical and pathological findings in a case of congenital inclusion disease." J Med Virol 67(2): 200-6.

The human cytomegalovirus (HCMV), a member of the Herpesviridae, is the most frequent cause of congenital virus infections and a major cause of morbidity and mortality in immunocompromised patients. Due to the lack of an appropriate animal model, insight into the pathogenesis of HCMV infections originates primarily from in situ examination of HCMV-infected tissues. Although in immunocompromised adults such tests are complicated frequently by the presence of additional misleading pathogens, the absence of additional pathogens renders congenital inclusion disease the most suitable access for investigation of pathogenetic aspects of HCMV infections. Immunohistochemical examination of tissue sections from a boy with fatal congenital inclusion disease was undertaken to detect the extent of multiorgan and cell involvement. Adrenal gland, bone marrow, diencephalon, heart, kidney, liver, lung, pancreas, placenta, small bowel and spleen were included in this study. Detection of virus antigens from different phases of viral replication revealed that all investigated organs were infected by HCMV. Simultaneous detection of cell type specific marker molecules showed that a variety of cell types stained positive for HCMV antigens including endothelial cells, epithelial cells, smooth muscle cells, mesenchymal cells, hepatocytes, monocytes/macrophages and granulocytes. The lung, the pancreas, the kidneys and the liver were the major target organs with a high number of HCMV infected cells. This correlated with multiorgan failure as the cause of death and strongly indicates direct pathogenetic effects of HCMV.

Bodeus, M., M. Van Ranst, et al. (2002). "Anticytomegalovirus IgG avidity in pregnancy: a 2-year prospective study." Fetal Diagn Ther 17(6): 362-6.

OBJECTIVES: To analyze the practical use of the anticytomegalovirus IgG avidity and its impact on the follow-up of pregnancy. To evaluate the performance of IgG avidity to exclude the risk of congenital infection. METHODS: 409 IgM-positive women without a documented seroconversion were prospectively followed. Data concerning the follow-up of the pregnancies were collected (amniotic fluid puncture and samples from the offspring). These observations were compared to those of 76 seroconversions during the same period. RESULTS: High avidity excluding a primary infection within the past 3 months was observed in 270 women. As the gestational age was less than 3 months for 121 women, exclusion of a primary infection was achieved in 30% of the cases. The rate of amniotic fluid puncture was influenced by the serological result: high avidity (9%), low avidity (42%) and seroconversion (65%). CONCLUSIONS: A high avidity index during the first trimester of pregnancy could reasonably be considered as a good indicator of past infection and invasive prenatal diagnosis is not necessary. Nearly 70% of the IgM-positive women could be reassured if the first serology was systematically performed before 12 weeks of gestation.

Einsele, H., E. Roosnek, et al. (2002). "Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy." Blood 99(11): 3916-22.

We adoptively transferred donor-derived cytomegalovirus (CMV)-specific T-cell lines into 8 stem cell transplant recipients lacking CMV-specific T-cell proliferation. All patients, of whom one was infected by a CMV strain that was genotypically ganciclovir resistant, had received unsuccessful antiviral chemotherapy for more than 4 weeks. CMV-specific lines had been prepared by repetitive stimulation with CMV antigen, which increased the percentage of CMV-specific T cells and ablated alloreactivity completely even against patients mismatched for 1 to 3 HLA antigens. After transfer of 10(7) T cells/m(2) at a median of 120 days (range, 79-479 days) after transplantation, no side effects were noticed. Despite cessation of antiviral chemotherapy, the CMV load dropped significantly in all 7 evaluable patients, with a maximal reduction after a median of 20 days (range, 5-31 days). In 2 patients with high virus load, the antiviral effect was only transient. One of these patients received a second T-cell infusion, which cleared the virus completely. At a median of 11 days after transfer, CMV-specific T-cell proliferation was demonstrated in 6 patients, and an increase in CMV-specific CD4(+) T cells was demonstrated in 5 patients. In 6 patients, 1.12 to 41 CMV-specific CD8(+) T cells/microL blood were detected at a median of 13 days after transfer, with an increase in all patients lacking CMV-specific CD8(+) T cells prior to transfer. Hence, anti-CMV cellular therapy was successful in 5 of 7 patients, whereas in 2 of 7 patients, who received an intensified immune suppression at the time of or after T-cell therapy, only transient reductions in virus load were obtained.

Maidji, E., E. Percivalle, et al. (2002). "Transmission of human cytomegalovirus from infected uterine microvascular endothelial cells to differentiating/invasive placental cytotrophoblasts." Virology 304(1): 53-69.

Analysis of placentas infected with human cytomegalovirus (CMV) suggested that viral transmission could involve differentiating/invasive cytotrophoblasts in villi that attach the placenta to the uterine wall. To parse the cellular components in this process, we developed a coculture system of polarized uterine microvascular endothelial cell (UtMVEC) infection with an endothelial cell-tropic pathogenic strain of CMV. Then we evaluated the potential role of neutrophils and endothelial cells in the spread of infection to differentiating cytotrophoblasts. As shown by immunocytochemistry and analysis of viral replication, CMV preferentially infected endothelial cells via apical membranes and disrupted cell junction proteins, thereby altering paracellular permeability and cell polarity. Neutralizing antibodies to CMV glycoprotein B, an envelope component that facilitates virion penetration, blocked plaque formation in polarized UtMVEC. Neutrophils transmitted CMV infection to UtMVEC, which in turn infected cytotrophoblasts. However, neutrophils did not directly infect cytotrophoblasts. These findings implicate endothelial cells from the uterine microvasculature as a potential source for CMV infection of endovascular cytotrophoblasts of the anchoring villi. Possibly the cytokine/chemokine milieu in the pregnant uterus could attract immune cells that infect endothelial cells in hybrid fetal- maternal vessels. In turn, these cells could infect endovascular cytotrophoblasts, one possible initiation point of a cascade that results in retrograde placental CMV infection.

Mocarski, E. S. (2002). "Immunomodulation by cytomegaloviruses: manipulative strategies beyond evasion." Trends Microbiol. 10(7): 332-339.

Human cytomegalovirus (CMV) remains the major infectious cause of birth defects as well as an important opportunistic pathogen. Individuals infected with CMV mount a strong immune response that suppresses persistent viral replication and maintains life-long latency. Loss of immune control opens the way to virus reactivation and disease. The large number of immunomodulatory functions encoded by CMV increases the efficiency of infection, dissemination, reactivation and persistent infection in hosts with intact immune systems and could contribute to virulence in immunocompromised hosts. These functions modulate both the innate and adaptive arms of the immune response and appear to target cellular rather than humoral responses preferentially. CMV encodes a diverse arsenal of proteins focused on altering and/or mimicking: (1) classical and non-classical major histocompatibility complex (MHC) protein function; (2) leukocyte migration, activation and cytokine responses; and (3) host cell susceptibility to apoptosis. Evidence that the host evolves mechanisms to counteract virus immune modulation is also accumulating. Although immune evasion is certainly one clear goal of the virus, the pro-inflammatory impact of certain viral functions suggests that increased inflammation benefits viral dissemination. The ability of such viral functions to successfully 'face off' against the host immune system ensures the success of this pathogen in the human population and could provide key insights into disease mechanisms.

Pass, R. F. and R. L. Burke (2002). "Development of cytomegalovirus vaccines: prospects for prevention of congenital CMV infection." Semin Pediatr Infect Dis 13(3): 196-204.

Congenital cytomegalovirus (CMV) infection is an important cause of hearing, cognitive, and motor impairments that cannot be effectively prevented or treated by any current medical or public health interventions. A review of priorities for vaccine development by The Institute of Medicine of the National Academy of Sciences concluded that a vaccine to prevent congenital CMV infection should be a top priority for the United States. Evidence from clinical studies indicates that immunity to CMV can reduce the frequency and severity of disease. Laboratory investigations have identified structural and nonstructural CMV proteins that play a key role in eliciting protective immunity. The rationale for development of a CMV vaccine has been strengthened further by studies in experimental animals demonstrating the ability of immunization with subunit vaccines to prevent disease and transplacental transmission of virus. At least 4 CMV vaccines are in clinical trials, and advances in biotechnology are paving the way for additional novel vaccines.

Revello, M. G., M. Zavattoni, et al. (2002). "Diagnosis and outcome of preconceptional and periconceptional primary human cytomegalovirus infections." J. Infect. Dis. 186(4): 553-557.

Primary human cytomegalovirus (HCMV) infection occurring in pregnant women within 3 months before (preconceptional) or within 4 weeks after (periconceptional) the last menstrual period represents an as-yet- undefined risk to the fetus. One (9.1%) of 11 newborns born to 12 women with preconceptional infection was subclinically infected (1 aborted fetus was not examined for infection). Of 20 pregnancies in women with periconceptional infection, 7 were terminated before 12 weeks of gestation (aborted fetus was not examined), 1 was terminated at 23 weeks after prenatal diagnosis of congenital infection, and 12 continued to term. Of those 12, 3 resulted in newborns who were congenitally infected. Thus, in the periconceptional group, intrauterine transmission occurred in 4 (30.8%) of 13 pregnancies for which the virologic outcome was known. One newborn was symptomatic at birth, and disseminated HCMV infection was diagnosed in an aborted fetus. Periconceptional primary HCMV infection seems to bear a higher risk of unfavorable outcome than preconceptional infection, and counseling should be adjusted accordingly.

Rivera, L. B., S. B. Boppana, et al. (2002). "Predictors of hearing loss in children with symptomatic congenital cytomegalovirus infection." Pediatrics 110(4): 762-7.

OBJECTIVE: Congenital cytomegalovirus (CMV) infection is a major cause of sensorineural hearing loss (SNHL) and neurologic impairment in children. Although the majority of children with symptomatic congenital CMV infection develop hearing loss, many symptomatic infants have normal hearing. The purpose of this study was to identify indicators present in the newborn period that have predictive value for the development of hearing loss in children with symptomatic congenital CMV infection. METHODS: Of the 190 children who had symptomatic congenital CMV infection and were born between 1966 and 1997 and enrolled in a follow-up study, hearing outcome was known for 180 children. Follow-up data were analyzed using univariate and multivariate logistic regression analyses to determine the specific demographic, newborn clinical, and laboratory findings predictive of hearing loss. The amount of infectious CMV in urine was quantified in a subset of 21 children who were born between 1994 and 1998. RESULTS: The presence of intrauterine growth retardation, petechiae, hepatosplenomegaly, hepatitis, thrombocytopenia, and intracerebral calcifications was associated with the development of hearing loss on univariate analysis. The presence of microcephaly and other neurologic abnormalities was not predictive of hearing loss. Logistic regression analysis revealed that only petechiae and intrauterine growth retardation independently predicted hearing loss. None of the demographic and other newborn findings predicted progressive hearing loss. The children who developed hearing loss had higher urine CMV titers during infancy than those with normal hearing. CONCLUSION: In children with symptomatic congenital CMV infection, evidence of disseminated infection with or without the presence of neurologic involvement at birth was predictive of the development of hearing loss. However, it was not possible to identify factors that are independently predictive of the development of progressive hearing loss.

Spencer, J. V., K. M. Lockridge, et al. (2002). "Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10." J. Virol. 76(3): 1285-1292.

Cytomegalovirus (CMV) has highly evolved mechanisms for avoiding detection by the host immune system. Recently, in the genomes of human and primate CMV, a novel gene comprising segments of noncontiguous open reading frames was identified and found to have limited predicted homology to endogenous cellular interleukin-10 (IL-10). Here we investigate the biological activities of the CMV IL-10-like gene product and show it to possess potent immunosuppressive properties. Both purified bacterium-derived recombinant CMV IL-10 and CMV IL-10 expressed in supernatants of human cells were found to inhibit proliferation of mitogen-stimulated peripheral blood mononuclear cells (PBMCs), with specific activity comparable to that of recombinant human IL-10. In addition, CMV IL-10 expressed from human cells inhibited cytokine synthesis, as treatment of stimulated PBMCs and monocytes with CMV IL-10 led to a marked decrease in production of proinflammatory cytokines. Finally, CMV IL-10 was observed to decrease cell surface expression of both major histocompatibility complex (MHC) class I and class II molecules, while conversely increasing expression of the nonclassical MHC allele HLA-G. These results demonstrate for the first time that CMV has a biologically active IL-10 homolog that may contribute to immune evasion during virus infection.

Compton, T., E. A. Kurt-Jones, et al. (2003). "Human cytomegalovirus activates inflammatory cytokine responses via CD14 and toll-Like receptor 2." J Virol 77(8): 4588-96.

Human cytomegalovirus (CMV) is a ubiquitous opportunistic pathogen that causes significant morbidity and mortality in immuncompromised people. An understanding of how CMV induces and circumvents host immunity is of critical importance in efforts to design effective therapeutics. It was recently discovered that mere cell contact by CMV particles leads to profound modulation of cellular gene expression, including induction of inflammatory cytokines and interferon-stimulated genes characteristic of innate immune detection. These findings suggest that a membrane receptor recognizes a CMV envelope protein(s), leading to innate immune activation. Here, we show that the pattern recognition receptors Toll-like receptor 2 (TLR2) and CD14 recognize CMV virions and trigger inflammatory cytokine production. Induction of inflammatory cytokines is mediated via TLR2-dependent activation of NF-kappaB. Since many of the pathological processes associated with CMV disease are facilitated or directly mediated by inflammatory cytokines, identification of the host membrane detection machinery may ultimately lead to improved therapeutics.

Fowler, K. B., S. Stagno, et al. (2003). "Maternal immunity and prevention of congenital cytomegalovirus infection." Jama 289(8): 1008-11.

CONTEXT: Vaccine development to prevent congenital cytomegalovirus (CMV) infection has been impeded by the uncertainty over whether maternal immunity protects the fetus. OBJECTIVE: To determine whether the presence of maternal antibodies to CMV significantly reduces the risk of congenital CMV infection in future pregnancies. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of 3461 multiparous women from a population with a high rate of congenital CMV infection who delivered newborns screened for congenital CMV infection between 1993 and 1998, and whose cord serum specimen from a previous delivery could be retrieved and tested for antibody to CMV. MAIN OUTCOME MEASURE: Congenital CMV infection according to maternal immune status, age, race, parity, and socioeconomic status. RESULTS: Of 604 newborns born to initially seronegative mothers, congenital CMV infection occurred in 18 (3.0%). In contrast, of 2857 newborns born to immune mothers, congenital CMV infection occurred in 29 (1.0%) Two factors, preconception maternal immunity (adjusted risk ratio, 0.31; 95% confidence interval, 0.17-0.58) and maternal age of 25 years or older (adjusted risk ratio, 0.19; 95% confidence interval, 0.07-0.49), were highly protective against congenital CMV infection. No other factors were associated with a reduction in the risk of congenital CMV infection. CONCLUSION: Naturally acquired immunity results in a 69% reduction in the risk of congenital CMV infection in future pregnancies.

Kimberlin, D. W., C. Y. Lin, et al. (2003). "Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial." J Pediatr 143(1): 16-25.

OBJECTIVE: To evaluate the efficacy and safety of ganciclovir therapy in neonates with congenital cytomegalovirus (CMV) disease. STUDY DESIGN: Neonates with symptomatic CMV disease involving the central nervous system were randomly assigned to receive 6 weeks of intravenous ganciclovir versus no treatment. The primary end point was improved brainstem-evoked response (BSER) between baseline and 6-month follow-up (or, for patients with normal baseline hearing, normal BSER at both time points). RESULTS: From 1991 to 1999, 100 patients were enrolled. Of these, 42 patients had both a baseline and 6-month follow-up BSER audiometric examination and thus were evaluable for the primary end point. Twenty-one (84%) of 25 ganciclovir recipients had improved hearing or maintained normal hearing between baseline and 6 months versus 10 (59%) of 17 control patients (P=.06). None (0%) of 25 ganciclovir recipients had worsening in hearing between baseline and 6 months versus 7 (41%) of 17 control patients (P.01). A total of 43 patients had a BSER at both baseline and at 1 year or beyond. Five (21%) of 24 ganciclovir recipients had worsening of hearing between baseline and > or =1 year versus 13 (68%) of 19 control patients (P.01). A total of 89 patients had absolute neutrophil counts determined during the course of the study; 29 (63%) of 46 ganciclovir-treated patients had grade 3 or 4 neutropenia during treatment versus 9 (21%) of 43 control patients (P.01). CONCLUSIONS: Ganciclovir therapy begun in the neonatal period in symptomatically infected infants with CMV infection involving the central nervous system prevents hearing deterioration at 6 months and may prevent hearing deterioration at > or =1 year. Almost two thirds of treated infants have significant neutropenia during therapy.

Pereira, L., E. Maidji, et al. (2003). "Human cytomegalovirus transmission from the uterus to the placenta correlates with the presence of pathogenic bacteria and maternal immunity." J. Virol. 77: 13301-13314.

Prenatal cytomegalovirus infection may cause pregnancy complications such as intrauterine growth restriction and birth defects. How virus from the mother traverses the placenta is unknown. PCR analysis of biopsy specimens of the maternal-fetal interface revealed that DNA sequences from cytomegalovirus were commonly found with those of herpes simplex viruses and pathogenic bacteria. Cytomegalovirus DNA and infected cell proteins were found more often in the decidua than in the placenta, suggesting that the uterus functions as a reservoir for infection. In women with low neutralizing titers, cytomegalovirus replicated in diverse decidual cells and placental trophoblasts and capillaries. In women with intermediate to high neutralizing titers, decidual infection was suppressed and the placenta was spared. Overall, cytomegalovirus virions and maternal immunoglobulin G were detected in syncytiotrophoblasts, villus core macrophages, and dendritic cells. These results suggest that the outcome of cytomegalovirus infection depends on the presence of other pathogens and coordinated immune responses to viral replication at the maternal-fetal interface.

Sugiura, S., T. Yoshikawa, et al. (2003). "Detection of human cytomegalovirus DNA in perilymph of patients with sensorineural hearing loss using real-time PCR." J Med Virol 69(1): 72-5.

Although cytomegalovirus (CMV) has been detected in the inner ear fluid of patients who succumbed to the complications of symptomatic congenital CMV infection, it has not been detected in the inner ear fluid of living patients. In this study, real-time polymerase chain reaction (PCR) was used to measure CMV DNA in clinical samples (including perilymph) collected from five patients with deafness. In case 1, diagnosed as a symptomatic congenital CMV infection, 3 copies/microl of CMV DNA were detected in perilymph, although no viral DNA was detected in peripheral blood mononuclear cells (PBMCs) or urine samples. In case 4, a suspected asymptomatic congenital CMV infection, 36 copies/microg of CMV DNA were detected in PBMCs, but neither perilymph nor urine contained viral DNA. Likewise, in case 5, a case of deafness of unknown origin, 48 copies/microg of CMV DNA were detected in the PBMCs, but none in the perilymph or urine. CMV DNA was not detected in the samples obtained from the remaining two cases with deafness of unknown etiology. To our knowledge, this is the first report to detect CMV DNA in an inner ear sample obtained from a living human subject.

Wang, X., S. M. Huong, et al. (2003). "Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus." Nature 424: 456-61.

Human cytomegalovirus (HCMV) is a widespread opportunistic herpesvirus that causes severe and fatal diseases in immune-compromised individuals, including organ transplant recipients and individuals with AIDS. It is also a leading cause of virus-associated birth defects and is associated with atherosclerosis and coronary restenosis. HCMV initiates infection and intracellular signalling by binding to its cognate cellular receptors and by activating several signalling pathways including those mediated by mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, interferons, and G proteins. But a cellular receptor responsible for viral entry and HCMV-induced signalling has yet to be identified. Here we show that HCMV infects cells by interacting with epidermal growth factor receptor (EGFR) and inducing signalling. Transfecting EGFR-negative cells with an EGFR complementary DNA renders non-susceptible cells susceptible to HCMV. Ligand displacement and crosslinking analyses show that HCMV interacts with EGFR through gB, its principal envelope glycoprotein. gB preferentially binds EGFR and EGFR-ErbB3 oligomeric molecules in Chinese hamster ovary cells transfected with erbB family cDNAs. Taken together, these data indicate that EGFR is a necessary component for HCMV-triggered signalling and viral entry.

Andrews, J. I. (2004). "Diagnosis of fetal infections." Curr Opin Obstet Gynecol 16(2): 163-6.

PURPOSE OF REVIEW: The purpose of this review is to present recent developments in the prenatal diagnosis of the most clinically relevant congenital infections. RECENT FINDINGS: Immunoglobin G avidity testing can help to differentiate between recent or prior infection. A combination of tests, including serology, avidity and polymerase chain reaction, may be necessary to improve accuracy of diagnosis. The interval between exposure to an infectious agent and prenatal testing can be critical to the interpretation of the test result. SUMMARY: This review reinforces the need for accurate testing to guide appropriate counseling and individual fetal risk assessment. The findings of viral-specific antibodies or sonographic abnormalities do not accurately predict the severity or outcome of fetal infection. Further research is necessary to determine the pathogenesis of transplacental viral transmission and thereby allow us to target prevention strategies.

Burny, W., C. Liesnard, et al. (2004). "Epidemiology, pathogenesis and prevention of congenital cytomegalovirus infection." Expert Rev Anti Infect Ther 2(6): 881-94.

Cytomegalovirus is the most common cause of congenital infection. Congenital cytomegalovirus infection can follow both primary and recurrent maternal infections. It is associated with a significant burden of disease and death. The determinants of mother-to-child transmission and the pathogenesis of symptomatic fetal infection remain poorly understood. For a long time, congenital cytomegalovirus infection has been a neglected disease. Recently, the Institute of Medicine has recognized that the development of a vaccine against congenital cytomegalovirus infection is a public health priority, which should stimulate research in this area. The development of antiviral therapies to prevent symptoms in infected newborns also represents an important area of research.

Chen, S. F., W. W. Tu, et al. (2004). "Antiviral CD8 T cells in the control of primary human cytomegalovirus infection in early childhood." J Infect Dis 189(9): 1619-27.

Human cytomegalovirus (CMV) establishes persistent infection, with control of replication thought to be mediated by CMV-specific CD8 T cells. Primary CMV infection commonly affects young children and causes prolonged viral shedding in saliva and urine. We investigated whether this virus-host interaction pattern reflects a developmental deficiency of antiviral CD8 T cell-mediated immunity during childhood. CMV-specific CD8 T cell responses in asymptomatic children with active infection were not different from adults with recent or long-term infection in frequency and functional analyses. High urine CMV concentrations were detected, despite these CMV-specific CD8 T cell responses. We conclude that delayed resolution of primary CMV infection in young children is not caused by a deficient CMV-specific CD8 T cell response. Because these healthy children continue to have local CMV replication, we suggest that CD8 T cells may function primarily to prevent symptomatic, disseminated disease.

Feire, A. L., H. Koss, et al. (2004). "Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain." Proc. Natl. Acad. Sci. U.S.A. 101: 15470-15475.

Human cytomegalovirus (HCMV) is capable of manifesting disease in nearly every organ system in immunocompromised patients. This broad pathogenic tropism correlates with the ability of the virus to infect all tested vertebrate cell types in vitro, a characteristic that has made receptor identification extremely difficult. During virus entry, HCMV induces cellular morphological changes and signaling cascades consistent with engagement of cellular integrins; however, HCMV structural proteins do not possess the widely used RGD integrin-binding motif. We identified an integrin-binding disintegrin-like domain within HCMV envelope glycoprotein B, a protein required for virus entry and fusion throughout the Herpesviridae. Accepted receptor criteria are met through the use of function-blocking integrin Abs, beta1 integrin knockout mouse fibroblasts, and glycoprotein B disintegrin-like peptides, all of which support a critical role for alpha2beta1, alpha6beta1, and alphaVbeta3 integrins as HCMV entry receptors and signaling mediators acting during the penetration stage of the entry pathway. Strikingly, the glycoprotein B disintegrin-like domain is conserved in many human and animal herpesviruses, suggesting that integrins may support entry across this medically important virus family.

Fowler, K. B., S. Stagno, et al. (2004). "Interval between births and risk of congenital cytomegalovirus infection." Clin Infect Dis 38(7): 1035-7.

To examine the effect of the interval between maternal cytomegalovirus (CMV) infection and conception on the risk of congenital CMV infection, the congenital CMV infection rate was evaluated relative to the intervals between deliveries in young women. Among mothers who seroconverted between deliveries, the rate of congenital CMV infection among their offspring was highest when the delivery interval was < or =24 months. However, the risk of transmission remained elevated for women with delivery intervals of 25-48 months and for those with delivery intervals >48 months apart.

McDonagh, S., E. Maidji, et al. (2004). "Viral and bacterial pathogens at the maternal-fetal interface." J. Infect. Dis. 190(4): 826-834.

We studied the incidence of pathogenic bacteria and concurrent infections with human cytomegalovirus (CMV) and herpes simplex virus (HSV) type 1 and 2 in biopsy samples from the placenta and decidua of women with healthy pregnancies. By polymerase chain reaction analysis, we found that 38% of placental samples were positive for selected bacteria and viruses. CMV, HSV-1, and HSV-2 were detected in isolation or with bacteria in first- and second-trimester samples. Certain bacteria were detected more often during the second trimester than during the first--Ureaplasma urealyticum, Mycoplasma hominis, and Gardnerella/Bifidobacterium species. In paired samples from first-trimester tissues, the detection rate for viruses, compared with most bacteria, was higher in the decidua than in the adjacent placenta. In contrast, bacteria were more frequently detected in placenta. Analyses of immunoglobulin G isolated from the placenta support the hypothesis that immune responses suppress CMV reactivation in the presence of pathogenic bacteria at the maternal-fetal interface.

Revello, M. G. and G. Gerna (2004). "Pathogenesis and prenatal diagnosis of human cytomegalovirus infection." J Clin Virol 29(2): 71-83.

Congenital human cytomegalovirus (HCMV) infection is the leading infectious cause of mental retardation and sensorineural deafness. Intrauterine transmission and adverse outcome are mainly related to primary maternal infection. Mechanisms of intrauterine transmission are slowly being unraveled and compelling evidence of the importance of using HCMV clinical strains rather than laboratory-adapted strains for in vitro studies is growing. In the absence of a vaccine or a specific antiviral therapy which could be safely administered to pregnant women with primary HCMV infection, the option of prenatal diagnosis has a crucial role in the management of pregnancy complicated by primary HCMV infection. Reliability of prenatal results, however, is still a major concern presenting the risk of either false-negative or false-positive results. However, as more light is shed on the natural history of HCMV infection during pregnancy and fetal life, the predictive value of negative prenatal diagnosis results is becoming more defined, thus improving the quality of counseling. In addition, the availability of different assays for detection of HCMV in both fetal blood and amniotic fluid samples will eventually reduce the risk of false-positive results. Finally, the identification of reliable prognostic markers of fetal disease remains the ultimate goal and a major challenge.

Tu, W., S. Chen, et al. (2004). "Persistent and selective deficiency of CD4+ T cell immunity to cytomegalovirus in immunocompetent young children." J Immunol 172(5): 3260-7.

Healthy young children who acquire CMV have prolonged viral shedding into the urine and saliva, but whether this is attributable to limitations in viral-specific immune responses has not been explored. In this study, we found that otherwise immunocompetent young children after recent primary CMV infection accumulated markedly fewer CMV-specific CD4(+) T cells that produced IFN-gamma than did adults. These differences in CD4(+) T cell function persisted for more than 1 year after viral acquisition, and did not apply to CMV-specific IFN-gamma production by CD8(+) T cells. The IFN-gamma-producing CD4(+) T cells of children or adults that were reactive with CMV Ags were mainly the CCR7(low) cell subset of memory (CD45R0(high)CD45RA(low)) cells. The decreased IFN-gamma response to CMV in children was selective, because their CCR7(low) memory CD4(+) T cells and those of adults produced similar levels of this cytokine after stimulation with staphylococcal enterotoxin B superantigen. CD4(+) T cells from children also had reduced CMV-specific IL-2 and CD154 (CD40 ligand) expression, suggesting an early blockade in the differentiation of viral-specific CD4(+) T cells. Following CMV acquisition, children, but not adults, persistently shed virus in urine, and this was observable for at least 29 mo postinfection. Thus, CD4(+) T cell-mediated immunity to CMV in humans is generated in an age-dependent manner, and may have a substantial role in controlling renal viral replication and urinary shedding.

Yamamoto-Tabata, T., S. McDonagh, et al. (2004). "Human cytomegalovirus interleukin-10 downregulates matrix metalloproteinase activity and impairs endothelial cell migration and placental cytotrophoblast invasiveness in vitro." J. Virol. 78: 2831-2840.

At the uterine-placental interface, fetal cytotrophoblasts invade the decidua, breach maternal blood vessels, and form heterotypic contacts with uterine microvascular endothelial cells. In early gestation, differentiating/invading cytotrophoblasts produce high levels of matrix metalloproteinase-9 (MMP-9), which degrades the extracellular matrix and increases invasion depth. By midgestation, when invasion is complete, MMP levels are reduced. Cytotrophoblasts also produce human interleukin-10 (hIL-10), a pleiotropic cytokine that modulates immune responses, helping to protect the fetal hemiallograft from rejection. Human cytomegalovirus (CMV) is often detected at the uterine-placental interface. CMV infection impairs cytotrophoblast differentiation/invasion, altering expression of the cells’ adhesion and immune molecules. Here we report that infection with a clinical CMV strain, VR1814, but not a laboratory strain, AD169, downregulated MMP activity in uterine microvascular endothelial cells and differentiating/invading cytotrophoblasts. Infected cytotrophoblasts expressed CMV IL-10 (cmvIL-10) mRNA and secreted the viral cytokine, which upregulated hIL-10. Functional analyses showed that cmvIL-10 treatment impaired migration in endothelial cell wounding assays and cytotrophoblast invasion of Matrigel in vitro. Comparable changes occurred in cells exposed to recombinant hIL-10 or cmvIL-10. Our results show that cmvIL-10 decreases MMP activity and dysregulates the cell-cell and/or cell-matrix interactions of infected cytotrophoblasts and endothelial cells. Reduced MMP activity early in placental development could impair cytotrophoblast remodeling of the uterine vasculature and eventually restrict fetal growth in affected pregnancies.

Boppana, S. B., K. B. Fowler, et al. (2005). "Congenital cytomegalovirus infection: association between virus burden in infancy and hearing loss." J Pediatr 146(6): 817-23.

OBJECTIVE: To determine the relationship between the virus burden in infancy and hearing loss in congenital CMV infection. STUDY DESIGN: A cohort of 76 infants with congenital cytomegalovirus (CMV) infection identified by means of newborn virologic screening was monitored for outcome. The amount of infectious CMV was analyzed in urine specimens obtained during early infancy. Peripheral blood (PB) samples obtained during early infancy were available from 75 children and CMV DNA was quantitated with a real-time quantitative polymerase chain reaction. RESULTS: Infants with clinical abnormalities at birth (symptomatic congenital CMV infection) had higher amounts of CMV in urine (P = .005) and CMV DNA in PB (P = .001) than infants with no symptoms. Eight children with and 4 children without symptoms had hearing loss. Among children without symptoms, those with hearing loss had a significantly greater amount of CMV in urine (P = .03) and PB virus burden (P = .02) during infancy than those with normal hearing. Infants with < 5 x 10(3) pfu/mL of urine CMV and infants with < 1 x 10(4) copies/mL of viral DNA in PB were at a lower risk for hearing loss. CONCLUSION: In children with asymptomatic congenital CMV infection, hearing loss was associated with increased amounts of urine CMV and PB CMV DNA during early infancy.

Cannon, M. J. and K. F. Davis (2005). "Washing our hands of the congenital cytomegalovirus disease epidemic." BMC Public Health 5: 70.

BACKGROUND: Each year in the United States, an estimated 40,000 children are born with congenital cytomegalovirus (CMV) infection, causing an estimated 400 deaths and leaving approximately 8000 children with permanent disabilities such as hearing or vision loss, or mental retardation. More children are affected by serious CMV-related disabilities than by several better-known childhood maladies, including Down syndrome, fetal alcohol syndrome, and spina bifida. DISCUSSION: Congenital CMV is a prime target for prevention not only because of its substantial disease burden but also because the biology and epidemiology of CMV suggest that there are ways to reduce viral transmission. Because exposure to the saliva or urine of young children is a major cause of CMV infection among pregnant women, it is likely that good personal hygiene, especially hand-washing, can reduce the risk of CMV acquisition. Experts agree that such measures are likely to be efficacious (i.e., they will work if consistently followed) and the American College of Obstetricians and Gynecologists recommends that physicians counsel pregnant women about preventing CMV acquisition through careful attention to hygiene. However, because of concerns about effectiveness (i.e., Will women consistently follow hygienic practices as the result of interventions?), the medical and public health communities appear reluctant to embrace primary CMV prevention via improved hygienic practices, and educational interventions are rare. Current data on the effectiveness of such measures in preventing CMV infection are promising, but limited. There is strong evidence, however, that educational interventions can prevent other infectious diseases with similar transmission modes, suggesting that effective interventions can also be found for CMV. Until a CMV vaccine becomes available, effective educational interventions are needed to inform women about congenital CMV prevention. SUMMARY: Perhaps no single cause of birth defects and developmental disabilities in the United States currently provides greater opportunity for improved outcomes in more children than congenital CMV. Given the present state of knowledge, women deserve to be informed about how they can reduce their risk of CMV infection during pregnancy, and trials are needed to identify effective educational interventions.

Daiminger, A., U. Bader, et al. (2005). "Pre- and periconceptional primary cytomegalovirus infection: risk of vertical transmission and congenital disease." Bjog 112(2): 166-72.

OBJECTIVE: To estimate the risk of congenital cytomegalovirus infection and disease following primary maternal infection around the time of conception compared with the risk during later stages of pregnancy. DESIGN: Cohort study between 1990 and 2003. SETTING: Germany. PARTICIPANTS: One hundred and sixty-six pregnant women with serologically confirmed primary cytomegalovirus infection and known outcome. METHODS: Timing of primary cytomegalovirus infection by analysing the kinetics of cytomegalovirus-specific IgG and IgM antibodies, the IgG avidity index and neutralising antibodies. MAIN OUTCOME MEASURE: Onset of maternal primary infection in relation to congenital infection and disease. RESULTS: Preconceptional (between eight and two weeks before onset of the last menstrual period) was determined in three women and did not lead to congenital infection. Periconceptional infection (between one week before and five weeks after last menstrual period) occurred in 20 women with congenital infection in nine cases (45%). Timing was less precise (between eight weeks before and five weeks after last menstrual period) in an additional 10 women, three cases of which resulted in congenital infection. Of the 12 pregnancies in which congenital infection occurred, seven were terminated, six before the 12th week of gestation (WG 12) and one at WG 19 due to fetal hyperechogenic bowel. One of the five infected live-born infants delivered to a mother with periconceptional infection showed dystrophy and mild microcephaly at birth, but had a rather normal development at two years of age. Primary infections occurring between WG 6-20 and WG 20-38 resulted in transmission rates of 30% (27/89) and 58% (18/31), respectively. CONCLUSIONS: Counselling of women with periconceptional primary cytomegalovirus infection should be adjusted to offer prenatal diagnosis and high-level ultrasound controls due to the considerable risk for fetal infection and uncertainty of clinical outcome and disease.

Morello, C. S., M. Ye, et al. (2005). "Systemic priming-boosting immunization with a trivalent plasmid DNA and inactivated murine cytomegalovirus (MCMV) vaccine provides long-term protection against viral replication following systemic or mucosal MCMV challenge." J Virol 79(1): 159-75.

We previously demonstrated that vaccination of BALB/c mice with a pool of 13 plasmid DNAs (pDNAs) expressing murine cytomegalovirus (MCMV) genes followed by formalin-inactivated MCMV (FI-MCMV) resulted in complete protection against viral replication in the spleen and salivary glands following sublethal intraperitoneal (i.p.) challenge. Here, we found that following intranasal (i.n.) challenge, titers of virus in the lungs of the immunized mice were reduced approximately 1,000-fold relative to those for mock-immunized controls. We next sought to extend these results and to determine whether similar protection levels could be achieved by priming with a pool of three pDNAs containing three key plasmids (IE1, M84, and gB). We found that the three-pDNA priming elicited IE1- and M84-p65-specific CD8+ T lymphocytes and, following FI-MCMV boost, high levels of virion-specific immunoglobulin G (IgG) and virus-neutralizing antibodies. When mice were i.n. challenged 4 months after the last boost, titers of virus in the lungs of immunized mice were reduced 1,000- to 2,000-fold from those for controls during the peak of viral replication. Additionally, titers of virus were either at or below the detection limits for the salivary glands, liver, and spleen of the majority of the immunized mice. Following sublethal i.p. challenge, virus was undetectable in all of the above target organs of the immunized mice. Virion-specific IgA in the lungs was consistently detected by day 6 post-i.n. challenge for the immunized mice and by day 14 for controls. These results demonstrate the immunity and high levels of protection of the priming-boosting vaccination against both systemic and mucosal challenge.

Munro, S. C., B. Hall, et al. (2005). "Diagnosis of and screening for cytomegalovirus infection in pregnant women." J Clin Microbiol 43(9): 4713-8.

No single diagnostic test for cytomegalovirus (CMV) infection is currently available for pregnant women at all stages of gestation. Improved accuracy in estimating the timing of primary infections can be used to identify women at higher risk of giving birth to congenitally infected infants. A diagnostic algorithm utilizing immunoglobulin G (IgG), IgM, and IgG avidity was used to prospectively screen serum from 600 pregnant women enrolled from two groups: or =20 weeks gestation (n = 396) or 20 weeks gestation (n = 204). PCR testing of urine and/or blood was performed on all seropositive women (n = 341). The majority (56.8%) of women were CMV IgG seropositive, with 5.5% being also CMV IgM positive. In the IgM-positive women, 1.2% had a low-avidity IgG, indicating a primary CMV infection and a high risk of intrauterine transmission. Two infants with asymptomatic CMV infection were born of mothers who had seroconverted in the second trimester of pregnancy. Baseline, age-stratified CMV serostatus was established from 1,018 blood donors. Baseline seropositivity from a blood donor population increased with age from 34.9% seroprevalence at less than 20 years of age to 72% seroprevalence at 50 years of age. Women at high risk of intrauterine transmission of CMV were identified at all stages of gestation. Women infected with CMV during late gestation may be more likely to transmit the virus, so failure to detect seroconversions in late gestation may result in failure to detect infected neonates.

Munro, S. C., D. Trincado, et al. (2005). "Symptomatic infant characteristics of congenital cytomegalovirus disease in Australia." J Paediatr Child Health 41(8): 449-52.

BACKGROUND: Human cytomegalovirus (CMV) is the most common cause of viral intrauterine infection. In utero transmission can occur during primary maternal infection, reactivation or reinfection of seropositive mothers. OBJECTIVE: To describe the aetiology and clinical features of infants diagnosed with congenital CMV and to document maternal factors that were presented. METHODS: Active national surveillance was initiated in 1999 in collaboration with the Australian Paediatric Surveillance Unit. RESULTS: Monthly notifications resulted in 70 cases of congenital CMV being identified between 1999 and 2003. Nearly all of the cases were symptomatic with the most common clinical sequelae reported in infected infants being jaundice, thrombocytopaenia, hepatomegaly, petechiae, purpura and splenomegaly. Almost half (43.5%) of the infants had central nervous system (CNS) complications, such as microcephaly, chorioretinitis, sensorineural hearing loss, intracranial calcifications, developmental delay or seizures, with over half presenting two or more CNS abnormalities. Maternal febrile illness was noted in 54.8% of the cases. The majority of mothers were primiparous (46.4%) or secundiparous (39.3%), indicating two different population groups at risk of primary CMV infection. CONCLUSION: This study documents symptomatic congenital CMV cases in Australia.

Nigro, G., S. P. Adler, et al. (2005). "Passive immunization during pregnancy for congenital cytomegalovirus infection." N Engl J Med 353: 1350-62.

BACKGROUND: Currently, there is no effective intervention for a primary cytomegalovirus (CMV) infection during pregnancy. METHODS: We studied pregnant women with a primary CMV infection. The therapy group comprised women whose amniotic fluid contained either CMV or CMV DNA and who were offered intravenous CMV hyperimmune globulin at a dose of 200 U per kilogram of maternal weight. A prevention group, consisting of women with a recent primary infection before 21 weeks' gestation or who declined amniocentesis, was offered monthly hyperimmune globulin (100 U per kilogram intravenously). RESULTS: In the therapy group, 31 women received hyperimmune globulin, only 1 (3 percent) of whom gave birth to an infant with CMV disease (symptomatic at birth and handicapped at two or more years of age), as compared with 7 of 14 women who did not receive hyperimmune globulin (50 percent). Thus, hyperimmune globulin therapy was associated with a significantly lower risk of congenital CMV disease (adjusted odds ratio, 0.02; 95 percent confidence interval, -infinity to 0.15; P 0.001). In the prevention group, 37 women received hyperimmune globulin, 6 (16 percent) of whom had infants with congenital CMV infection, as compared with 19 of 47 women (40 percent) who did not receive hyperimmune globulin. Thus, hyperimmune globulin therapy was associated with a significantly lower risk of congenital CMV infection (adjusted odds ratio, 0.32; 95 percent confidence interval, 0.10 to 0.94; P=0.04). Hyperimmune globulin therapy significantly (P 0.001) increased CMV-specific IgG concentrations and avidity and decreased natural killer cells and HLA-DR+ cells and had no adverse effects. CONCLUSIONS: Treatment of pregnant women with CMV-specific hyperimmune globulin is safe, and the findings of this nonrandomized study suggest that it may be effective in the treatment and prevention of congenital CMV infection. A controlled trial of this agent may now be appropriate.

Pass, R. F. (2005). "Congenital cytomegalovirus infection and hearing loss." Herpes 12(2): 50-5.

Sensorineural hearing loss is the most frequent sequela of congenital cytomegalovirus (CMV) infection, and epidemiological evidence also suggests that congenital CMV infection is responsible for a substantial proportion of sensorineural hearing loss in children. Hearing loss due to congenital CMV infection can be present at birth or can appear later, usually during the first year of life; it usually worsens as the infant or child ages. Follow-up of children with congenital CMV infection should include repeated audiological testing. Based on the benefits of early detection of hearing loss, one could propose screening all infants for congenital CMV infection so that those with hearing impairment can be identified as early as possible by appropriate audiological follow-up. Antiviral treatment that could improve hearing outcome, with a safety profile suitable for use in minimally ill infants, would clearly increase the benefit of universal screening for congenital CMV infection.

Pass, R. F., K. B. Fowler, et al. (2005). "Congenital cytomegalovirus infection following first trimester maternal infection: Symptoms at birth and outcome." J Clin Virol.

BACKGROUND: The relationship between gestational age at time of maternal cytomegalovirus (CMV) infection and outcome of fetal infection is not well defined because the timing of maternal infection is usually not known. OBJECTIVE: To determine whether congenital cytomegalovirus (CMV) infection following primary maternal infection during the first trimester of pregnancy is more likely to lead to central nervous system (CNS) sequelae than fetal infection due to maternal infection later in pregnancy. STUDY DESIGN: Using serum collected during pregnancy from mothers of newborns with congenital CMV infection, maternal infection was categorized as first trimester (<13 weeks) or later based on dates and results of IgG and IgM assays for CMV antibody. Outcome of congenital CMV infection was assessed by longitudinal fotlow-up of the infected cohort. RESULTS: Sensorineural hearing loss was found in 8/34 (24%) of children in the first trimester group, compared with 1/40 (2.5%) in the later infection group (P=0.01, relative risk, 9.6). Considering any CNS sequela (hearing loss, mental retardation, cerebral palsy, seizures, chorioretinitis) 11/34 (32%) first trimester cases were affected compared with 6/40 (15%) in the later infection group (P=0.07, relative risk 2.2). None of the later group had more than one sequela, compared with 4 (12%) of the first trimester group (P=0.04). CONCLUSIONS: Children with congenital CMV infection following first trimester maternal infection are more likely to have CNS sequelae, especially sensorineural hearing loss, than are those whose mothers were infected later in pregnancy. However, some degree of CNS impairment can follow even late gestational infection.

Pereira, L., E. Maidji, et al. (2005). "Insights into viral transmission at the uterine-placental interface." Trends Microbiol 13(4): 164-74.

During human gestation, viruses can cause intrauterine infections associated with pregnancy complications and fetal abnormalities. The ability of viruses to spread from the infected mother to the fetus arises from the architecture of the placenta, which anchors the fetus to the uterus. Placental cytotrophoblasts differentiate, assume an endothelial phenotype, breach uterine blood vessels and form a hybrid vasculature that amplifies the maternal blood supply for fetal development. Human cytomegalovirus - the major cause of congenital disease - infects the uterine wall and the adjacent placenta, suggesting adaptation for pathogen survival in this microenvironment. Infection of villus explants and differentiating and/or invading cytotrophoblasts offers an in vitro model for studying viruses associated with prenatal infections.

Wang, X., D. Y. Huang, et al. (2005). "Integrin alphavbeta3 is a coreceptor for human cytomegalovirus." Nat Med 11: 515-21.

Human cytomegalovirus (HCMV) is a widespread opportunistic pathogen that causes birth defects in newborns and severe disease in immunocompromised individuals. The broad tropism of HCMV infection suggests that it uses multiple receptors. We recently showed that the epidermal growth factor receptor (EGFR) serves as a receptor for HCMV. Here we show that HCMV also uses integrin alphavbeta3 as a coreceptor. Upon infection, HCMV glycoproteins gB and gH independently bind to EGFR and alphavbeta3, respectively, to initiate viral entry and signaling. alphavbeta3 then translocates to lipid rafts where it interacts with EGFR to induce coordinated signaling. The coordination between EGFR and alphavbeta3 is essential for the early events of HCMV infection, including viral entry, RhoA downregulation, stress-fiber disassembly and viral nuclear trafficking. Our findings support a model in which EGFR and alphavbeta3 work together as coreceptors for HCMV entry and signaling. This discovery is fundamental to understanding HCMV pathogenesis and developing treatment strategies targeted to viral receptors.

Jeon, J., M. Victor, et al. (2006). "Knowledge and awareness of congenital cytomegalovirus among women." Infect Dis Obstet Gynecol 2006: 80383.

BACKGROUND: Congenital cytomegalovirus (CMV) infection is a leading cause of disabilities in children, yet the general public appears to have little awareness of CMV. METHODS: Women were surveyed about newborn infections at 7 different geographic locations. RESULTS: Of the 643 women surveyed, 142 (22%) had heard of congenital CMV. Awareness increased with increasing levels of education (P .0001). Women who had worked as a healthcare professional had a higher prevalence of awareness of CMV than had other women (56% versus 16%, P .0001). Women who were aware of CMV were most likely to have heard about it from a healthcare provider (54%), but most could not correctly identify modes of CMV transmission or prevention. Among common causes of birth defects and childhood illnesses, women's awareness of CMV ranked last. CONCLUSION: Despite its large public health burden, few women had heard of congenital CMV, and even fewer were aware of prevention strategies.

Lanari, M., T. Lazzarotto, et al. (2006). "Neonatal cytomegalovirus blood load and risk of sequelae in symptomatic and asymptomatic congenitally infected newborns." Pediatrics 117(1): e76-83.

OBJECTIVE: Human cytomegalovirus (CMV) is a ubiquitous human-specific DNA virus and is the main cause of congenital virus infection in developed countries leading to psychomotor impairment and deafness. Diagnostic techniques for CMV detection have greatly improved during recent years with the advent of sophisticated serological and virological methods. The aim of the present study was to assess the diagnostic and prognostic value of detection and quantification of virus in neonatal blood samples of symptomatic and asymptomatic newborns with CMV congenital infection. METHODS: Between January 1997 and December 2003, we studied 99 newborns who were born to women with primary, recurrent, and undefined CMV infection during pregnancy. CMV congenital infection was identified by isolation of the virus in urine within the second week of life. Fifty-eight of 99 infants were infected and were assessed clinically for disease in the newborn period and classified as having symptomatic or asymptomatic infection on the basis of physical, instrumental, and laboratory findings. The infants were followed up from birth according to a protocol of the tertiary NICU at the University of Bologna in a prospective study of long-term sequelae of congenital infection. Forty-seven blood samples were obtained from 47 infants in the neonatal period: 34 were examined for pp65 antigenemia test and 44 for qualitative and quantitative polymerase chain reaction (PCR and qPCR). Sequelae at 12 months were evaluated in a group of 50 infants. RESULTS: Antigenemia was positive in only 10 of 34 samples of infected newborns (29.4% sensitivity). PCR was performed in 44 samples of infected newborns and was positive in all (100% sensitivity). qPCR showed a finding of > or =100 copies per 10(5) of polymorphonuclear leukocytes (PMNLs) in 39 of 44 samples; in the other 5 cases, the number of copies per 10(5) PMNLs was 100. Between symptomatic and asymptomatic newborns, the mean values of viral blood load determined by qPCR turned out to be significantly higher in symptomatic newborns. Mean values of neonatal blood viral load were statistically higher in newborns who developed sequelae than in those who did not. Of 20 children with a neonatal viral blood load of 1000 copies per 10(5) PMNLs, 19 did not develop sequelae (negative predictive value: 95%), whereas 2 of 3 with a viral blood load of 10,000 copies did develop sequelae. CONCLUSIONS: Different viremia value ranges are correlated to a different risk of sequelae: approximately 70% sequelae were found in newborns with a qPCR higher than 10,000 copies per 10(5) PMNLs. Low neonatal viral blood load detected by pp65 antigenemia test and qPCR was highly predictive of absence of sequelae: DNAemia 1000 copies per 10(5) PMNLs has a negative predictive value of 95%. As an independent predictive factor of outcome, neonatal viremia is another useful element for neonatal counseling and therapeutic choices in symptomatic and asymptomatic newborns.

Maidji, E., S. McDonagh, et al. (2006). "Maternal antibodies enhance or prevent cytomegalovirus infection in the placenta by neonatal fc receptor-mediated transcytosis." Am J Pathol 168: 1210-26.

How human cytomegalovirus (CMV) reaches the fetus across the placenta is unknown. The major viral cause of congenital disease, CMV infects the uterine-placental interface with varied outcomes depending on the strength of maternal humoral immunity and gestational age. Covering the surface of villi that float in blood, syncytiotrophoblasts express the neonatal Fc receptor (FcRn) that transports IgG for passive immunity. Immunohistochemical analysis of early-gestation biopsy specimens showed an unusual pattern of CMV replication proteins in underlying villus cytotrophoblasts, whereas syncytiotrophoblasts were spared. Found in placentas with low to moderate CMV-neutralizing antibody titers, this pattern suggested virion transcytosis across the surface. In contrast, syncytiotrophoblasts from placentas with high neutralizing titers contained viral DNA and caveolin-1-positive vesicles in which IgG and CMV glycoprotein B co-localized. In villus explants, IgG-virion transcytosis and macrophage uptake were blocked with trypsin-treatment and soluble protein A. Quantitative analysis in polarized epithelial cells showed that FcRn-mediated transcytosis was blocked by the Fc fragment of IgG, but not F(ab')(2). Our results suggest that CMV virions could disseminate to the placenta by co-opting the receptor-mediated transport pathway for IgG. These findings could explain the efficacy of hyperimmune IgG for treatment of primary CMV infection during gestation and support vaccination.

McDonagh, S., E. Maidji, et al. (2006). "Patterns of human cytomegalovirus infection in term placentas: a preliminary analysis." J Clin Virol 35(2): 210-5.

BACKGROUND: Primary maternal CMV infection is the major risk factor for symptomatic congenital infection as maternal immunity reduces the risk of transmission to the fetus. Analysis of first trimester placentas showed that virus replicates in the uterus and is transmitted to the placenta causing focal infection. OBJECTIVES AND STUDY DESIGN: We examined 78 term placentas from uncomplicated deliveries for the presence of CMV DNA and evaluated evidence of infection by means of immunohistological and serological analysis. RESULTS: PCR analysis of villus biopsy samples and decidua showed that CMV DNA was present in 62% of tissues. Seven placentas with neutralizing titers were further examined by immunohistology for expression of viral proteins. In placentas with high levels of CMV DNA, fetal blood vessels in the villus core contained neutrophils with viral replication proteins, and macrophages/dendritic cells with glycoprotein B (gB). Cord blood samples from 1 of 11 placentas contained CMV DNA, an indication of replication in the fetal compartment. In placentas with low levels of viral DNA, macrophage/dendritic cells in the villus core contained CMV gB. This pattern was comparable to that seen in early gestation placentas from women with strong neutralizing antibodies. CONCLUSIONS: The results show CMV replication proteins in focal areas of the placenta, implying virus transmission to the fetal circulation. These preliminary results suggest that the incidence of asymptomatic congenital CMV infection might be higher than currently estimated.

Pass, R. F., K. B. Fowler, et al. (2006). "Congenital cytomegalovirus infection following first trimester maternal infection: symptoms at birth and outcome." J Clin Virol 35(2): 216-20.

BACKGROUND: The relationship between gestational age at time of maternal cytomegalovirus (CMV) infection and outcome of fetal infection is not well defined because the timing of maternal infection is usually not known. OBJECTIVE: To determine whether congenital cytomegalovirus (CMV) infection following primary maternal infection during the first trimester of pregnancy is more likely to lead to central nervous system (CNS) sequelae than fetal infection due to maternal infection later in pregnancy. STUDY DESIGN: Using serum collected during pregnancy from mothers of newborns with congenital CMV infection, maternal infection was categorized as first trimester (13 weeks) or later based on dates and results of IgG and IgM assays for CMV antibody. Outcome of congenital CMV infection was assessed by longitudinal fotlow-up of the infected cohort. RESULTS: Sensorineural hearing loss was found in 8/34 (24%) of children in the first trimester group, compared with 1/40 (2.5%) in the later infection group (P=0.01, relative risk, 9.6). Considering any CNS sequela (hearing loss, mental retardation, cerebral palsy, seizures, chorioretinitis) 11/34 (32%) first trimester cases were affected compared with 6/40 (15%) in the later infection group (P=0.07, relative risk 2.2). None of the later group had more than one sequela, compared with 4 (12%) of the first trimester group (P=0.04). CONCLUSIONS: Children with congenital CMV infection following first trimester maternal infection are more likely to have CNS sequelae, especially sensorineural hearing loss, than are those whose mothers were infected later in pregnancy. However, some degree of CNS impairment can follow even late gestational infection.

Revello, M. G., M. Zavattoni, et al. (2006). "Preconceptional primary human cytomegalovirus infection and risk of congenital infection." J Infect Dis 193(6): 783-7.

The risk of vertical transmission of human cytomegalovirus (HCMV) was investigated in 14 women who had primary HCMV infection 2-18 weeks before their last menstrual period during 2001-2004. One (8.3%) of 12 newborns examined at birth was found to be subclinically infected. Preconceptional primary HCMV infection has a transmission rate that is significantly higher than that observed in an unselected newborn population but significantly lower than that associated with maternal infection during pregnancy. Although a safe time interval between primary infection and initiation of pregnancy still needs to be defined, documented information can now be provided during counseling.

Ross, D. S., S. C. Dollard, et al. (2006). "The epidemiology and prevention of congenital cytomegalovirus infection and disease: activities of the Centers for Disease Control and Prevention Workgroup." J Womens Health (Larchmt) 15(3): 224-9.

Perhaps no single cause of birth defects and developmental disabilities in the United States currently provides greater opportunity for improved outcomes in more children than congenital cytomegalovirus (CMV). --Cannon and Davis. BMC Public Health 2005;5:70 Each year in the United States, thousands of children and their families are affected by congenital cytomegalovirus (CMV) infection. More children may be affected by congenital CMV than by other, better known childhood conditions, such as Down syndrome, fetal alcohol syndrome, and spina bifida. The Centers for Disease Control and Prevention (CDC) has formed a Workgroup on Congenital CMV, led by the National Center on Birth Defects and Developmental Disabilities and the National Center on Infectious Diseases. This report provides background on congenital CMV infection and describes the goals and activities of the workgroup for reducing the burden of sequelae of congenital CMV infection.

Ross, S. A., K. B. Fowler, et al. (2006). "Hearing loss in children with congenital cytomegalovirus infection born to mothers with preexisting immunity." J Pediatr 148(3): 332-6.

OBJECTIVE: To define hearing outcomes in children with congenital cytomegalovirus (CMV) infection born to mothers with non-primary CMV infection. STUDY DESIGN: A cohort of 300 children with congenital CMV infection identified by newborn virologic screening at the University of Alabama Hospital and a private community hospital in which the type of maternal infection could be classified constituted the study population. Maternal infections were categorized by analyzing serum samples. Children were followed prospectively and underwent serial audiologic evaluations. RESULTS: The frequency of hearing loss was not different between children born to mothers with non-primary infection (10%) and those with primary infection (11%). Significantly more children in the primary infection group had progressive and severe/profound hearing loss compared with children in the non-primary group. The frequency of bilateral, delayed onset, high-frequency, and fluctuating hearing loss was not different between the 2 groups. The mean age of diagnosis of hearing loss was 39 +/- 53 months for children born to mothers with non-primary infection and 13 +/- 21 months for the primary infection group (P = .16). CONCLUSIONS: Maternal preexisting seroimmunity to CMV does not provide complete protection against hearing loss in infants with congenital CMV infection.

Staras, S. A., S. C. Dollard, et al. (2006). "Seroprevalence of cytomegalovirus infection in the United States, 1988-1994." Clin Infect Dis 43(9): 1143-51.

BACKGROUND: Cytomegalovirus (CMV) is a leading cause of congenital illness and disability, including hearing loss and mental retardation. However, there are no nationwide estimates of CMV seroprevalence among pregnant women or the overall population of the United States. METHODS: To determine CMV prevalence in a representative sample of the US population, we tested serum samples for CMV-specific immunoglobulin G from participants aged > or =6 years (n=21,639) in the third National Health and Nutrition Examination Survey (1988-1994). RESULTS: The prevalence of CMV infection was 58.9% in individuals > or =6 years old. CMV seroprevalence increased gradually with age, from 36.3% in 6-11-year-olds to 90.8% in those aged > or =80 years. CMV seroprevalence differed by race and/or ethnicity as follows: 51.2% in non-Hispanic white persons, 75.8% in non-Hispanic black persons, and 81.7% in Mexican Americans. Racial and/or ethnic differences in CMV seroprevalence persisted when controlling for household income level, education, marital status, area of residence, census region, family size, country of birth, and type of medical insurance. Among women, racial and/or ethnic differences were especially significant; between ages 10-14 years and 20-24 years, seroprevalence increased 38% for non-Hispanic black persons, 7% for non-Hispanic white persons, and <1% for Mexican Americans. CONCLUSIONS: On the basis of these results, we estimate that each year in the United States approximately 340,000 non-Hispanic white persons, 130,000 non-Hispanic black persons, and 50,000 Mexican American women of childbearing age experience a primary CMV infection. Given the number of women at risk and the significance of congenital disease, development of programs for the prevention of CMV infection, such as vaccination or education, is of considerable public health importance.

Adler, S. P., G. Nigro, et al. (2007). "Recent advances in the prevention and treatment of congenital cytomegalovirus infections." Semin Perinatol 31(1): 10-8.

Continued but slow progress has led to recent advances in our understanding that congenital cytomegalovirus (CMV) infection has occurred. We understand that the most severe congenital disease occurs following a primary maternal infection during pregnancy. We now have the ability to accurately diagnosis a primary maternal infection using serologic studies of single serum sample. For pregnant women with young children, we know that child-to-mother CMV transmission can probably be prevented by hygienic intervention, and that for pregnant women who have acquired a primary CMV infection, mother-to-fetal transmission is probably preventable using CMV hyperimmune globulin. Although additional studies are needed, treatment of congenitally infected fetuses or newborns should be possible using either CMV hyperimmune globulin or antiviral agents such as ganciclovir or its derivates. Finally, recent evidence indicates that CMV replicates in the placenta, impairs development, and causes inflammation and dysfunction. This plus the reversibility of many manifestations of congenital infection in the fetus and newborn indicate that congenital CMV disease is in part a syndrome of placental insufficiency.

Colugnati, F. A., S. A. Staras, et al. (2007). "Incidence of cytomegalovirus infection among the general population and pregnant women in the United States." BMC Infect Dis 7: 71.

ABSTRACT: BACKGROUND: Cytomegalovirus (CMV) is a common opportunistic infection among HIV-infected individuals, a major source of serious complications among organ-transplant recipients, and a leading cause of hearing loss, vision loss, and mental retardation among congenitally infected children. Women infected for the first time during pregnancy are especially likely to transmit CMV to their fetuses. More children suffer serious disabilities caused by congenital CMV than by several better-known childhood maladies such as Down syndrome or fetal alcohol syndrome METHODS: Using CMV seroprevalence data from the nationally representative Third National Health and Nutrition Examination Survey, we estimated CMV incidence among the general United States population and among pregnant women. We employed catalytic models that used age-specific CMV seroprevalences as cumulative markers of past infections in order to derive estimates of three basic parameters: the force of infection, the basic reproductive rate, and the average age of infection. Our main focus was the force of infection, an instantaneous per capita rate of acquisition of infection that approximates the incidence of infection in the seronegative population. RESULTS: Among the United States population ages 12-49 the force of infection was 1.6 infections per 100 susceptible persons per year (95% confidence interval: 1.2, 2.4). The associated basic reproductive rate of 1.7 indicates that, on average, an infected person transmits CMV to nearly two susceptible people. The average age of CMV infection was 28.6 years. Force of infection was significantly higher among non-Hispanic Blacks (5.7) and Mexican Americans (5.1) than among non-Hispanic Whites (1.4). Force of infection was significantly higher in the low household income group (3.5) than in the middle (2.1) and upper (1.5) household income groups. Based on these CMV incidence estimates, approximately 27,000 new CMV infections occur among seronegative pregnant women in the United States each year. CONCLUSION: These thousands of CMV infections in pregnant women, along with the sharp racial/ethnic disparities in CMV incidence, are compelling reasons for accelerating research on vaccines and other interventions for preventing congenital CMV disease. Nevertheless, the relatively low force of infection provides encouraging evidence that modestly effective vaccines and rates of vaccination could significantly reduce CMV transmission.

Kenneson, A. and M. J. Cannon (2007). "Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection." Rev Med Virol 17(4): 253-76.

We reviewed studies that reported results of systematic cytomegalovirus (CMV) screening on fetuses and/or live-born infants. The overall birth prevalence of congenital CMV infection was 0.64%, but varied considerably among different study populations. About 11% of live-born infants with congenital CMV infection were symptomatic, but the inter-study differences in definitions of symptomatic cases limit the interpretation of these data. Non-white race, low socioeconomic status (SES), premature birth, and neonatal intensive care unit admittance were risk factors for congenital CMV infection. Birth prevalence increased with maternal CMV seroprevalence. Maternal seroprevalence accounted for 29% of the variance in birth prevalence between study populations. Maternal seroprevalence and birth prevalence were both higher in study populations that were ascertained at birth rather than in the prenatal period. Thus, timing of ascertainment should be considered when interpreting birth prevalence estimates. Birth prevalence was inversely correlated with mean maternal age, but this relationship was not significant when controlling for maternal seroprevalence. The rate of transmission to infants born to mothers who had a primary infection or a recurrent infection during pregnancy was 32% and 1.4%, respectively. Possible maternal primary infections (i.e. seropositive mother with CMV IgM) resulted in congenital infections about 20% of the time, but are likely to represent a mixture of primary and recurrent infections. In summary, CMV is a common congenital infection worldwide that can lead to permanent disabilities. There is an urgent need for interventions that can reduce the substantial burden of this often overlooked disease.

Maidji, E., O. Genbacev, et al. (2007). "Developmental regulation of human cytomegalovirus receptors in cytotrophoblasts correlates with distinct replication sites in the placenta." J Virol 81(9): 4701-12.

Cytomegalovirus (CMV), the major viral cause of congenital disease, infects the uterus and developing placenta and spreads to the fetus throughout gestation. Virus replicates in invasive cytotrophoblasts in the decidua, and maternal immunoglobulin G (IgG)-CMV virion complexes, which are transcytosed by the neonatal Fc receptor across syncytiotrophoblasts, infect underlying cytotrophoblasts in chorionic villi. Immunity is central to protection of the placenta-fetal unit: infection can occur when IgG has a low neutralizing titer. Here we used immunohistochemical and function-blocking methods to correlate infection in the placenta with expression of potential CMV receptors in situ and in vitro. In placental villi, syncytiotrophoblasts express the virion receptor epidermal growth factor receptor (EGFR) but lack integrin coreceptors, and virion uptake occurs without replication. Focal infection can occur when transcytosed virions reach EGFR-expressing cytotrophoblasts that selectively initiate expression of alphaV integrin. In cell columns, proximal cytotrophoblasts lack receptors and distal cells express integrins alpha1beta1 and alphaVbeta3, enabling virion attachment. In the decidua, invasive cytotrophoblasts expressing coreceptors upregulate EGFR, thereby dramatically increasing susceptibility to infection. Our findings indicate that virion interactions with cytotrophoblasts expressing receptors in the placenta (i) change as the cells differentiate and (ii) correlate with spatially distinct sites of CMV replication in maternal and fetal compartments.

Morello, C. S., L. A. Kelley, et al. (2007). "DNA immunization using highly conserved murine cytomegalovirus genes encoding homologs of human cytomegalovirus UL54 (DNA polymerase) and UL105 (helicase) elicits strong CD8 T-cell responses and is protective against systemic challenge." J Virol 81(14): 7766-75.

Human cytomegalovirus (HCMV) establishes a lifelong infection with the potential for reinfection or viral transmission even in the presence of strong and diverse CD8 T-lymphocyte responses. This suggests that the CMVs skew the host T-cell response in order to favor viral persistence. In this study, we hypothesized that the essential, nonstructural proteins that are highly conserved among the CMVs may represent a novel class of T-cell targets for vaccine-mediated protection due to their requirements for expression and sequence stability, but that the observed subdominance of these antigens in the CMV-infected host results from the virus limiting the T-cell responses to otherwise-protective specificities. We found that DNA immunization of mice with the murine CMV (MCMV) homologs of HCMV DNA polymerase (M54) or helicase (M105) was protective against virus replication in the spleen following systemic challenge, with the protection level elicited by the M54 DNA being comparable to that of DNA expressing the immunodominant IE1 (pp89). Intracellular gamma interferon staining of CD8 T cells from mice immunized with either the M54 or M105 DNAs showed strong primary responses that recalled rapidly after viral challenge. M54- and M105-specific CD8 T cells were detected after the primary MCMV infection, but their levels were not consistently above the background level. The conserved, essential proteins of the CMVs thus represent a novel class of CD8 T-cell targets that may contribute to a successful HCMV vaccine strategy.

Tabata, T., S. McDonagh, et al. (2007). "Cytotrophoblasts infected with a pathogenic human cytomegalovirus strain dysregulate cell-matrix and cell-cell adhesion molecules: a quantitative analysis." Placenta 28(5-6): 527-37.

Studies of intrauterine human cytomegalovirus (CMV) infection have shown suppressed replication in the decidua and placenta of strongly seropositive women. Biopsy specimens often contain CMV virion glycoprotein B and DNA in syncytiotrophoblasts and villus core macrophages without productive infection. Focal replication occurs in placentas of women with low to moderate neutralizing antibody titres. Infected cytotrophoblasts downregulate key adhesion and immune molecules required for invasiveness and maternal immune tolerance and reduce matrix metalloproteinase-9 protein and activity, impairing degradation of the extracellular matrix. Here, we used flow cytometry and quantitative RT-PCR analyses to quantify differentiation molecules expressed in freshly isolated cytotrophoblasts purified from placentas at term and differentiating cells infected in vitro with VR1814, a pathogenic clinical strain. Cell surface proteins including E-cadherin, VE-cadherin, HLA-G, and CMV receptors--epidermal growth factor receptor and integrins beta1 and alphavbeta3--were expressed on purified cells, as were integrins alpha9 and beta6, which were not previously studied. Infected cytotrophoblasts dysregulate the levels of particular cell-matrix and cell-cell adhesion proteins and their transcripts. CMV replication in late gestation placentas with considerable reserves could deplete cytotrophoblast progenitors, thereby impairing syncytiotrophoblast development and increasing the risk of virus transmission to fetal blood vessels.

Yue, Y., A. Kaur, et al. (2007). "Immunogenicity and protective efficacy of DNA vaccines expressing rhesus cytomegalovirus glycoprotein B, phosphoprotein 65-2, and viral interleukin-10 in rhesus macaques." J Virol 81(3): 1095-109.

Rhesus cytomegalovirus (RhCMV) infection of macaques exhibits strong similarities to human CMV (HCMV) persistence and pathogenesis. The immunogenicity of DNA vaccines encoding three RhCMV proteins (a truncated version of glycoprotein B lacking the transmembrane region and endodomain [gBDeltaTM], phosphoprotein 65-2 [pp65-2], and viral interleukin-10 [vIL-10]) was evaluated in rhesus macaques. Two groups of monkeys (four per group) were genetically immunized four times with a mixture of either pp65-2 and gBDeltaTM or pp65-2, vIL-10, and gBDeltaTM. The vaccinees developed anti-gB and anti-pp65-2 antibodies in addition to pp65-2 cellular responses after the second booster immunization, with rapid responses observed with subsequent DNA injections. Weak vIL-10 immune responses were detected in two of the four immunized animals. Neutralizing antibodies were detected in seven monkeys, although titers were weak compared to those observed in naturally infected animals. The immunized monkeys and naive controls were challenged intravenously with 10(5) PFU of RhCMV. Anamnestic binding and neutralizing antibody responses were observed 1 week postchallenge in the vaccinees. DNA vaccination-induced immune responses significantly decreased peak viral loads in the immunized animals compared to those in the controls. No difference in peak viral loads was observed between the pp65-2/gBDeltaTM DNA- and pp65-2/vIL-10/gBDeltaTM-vaccinated groups. Antibody responses to nonvaccine antigens were lower postchallenge in both vaccine groups than in the controls, suggesting long-term control of RhCMV protein expression. These data demonstrated that DNA vaccines targeting the RhCMV homologues of HCMV gB and pp65 altered the course of acute and persistent RhCMV infection in a primate host.

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