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follows primary maternal rubella virus infection during pregnancy and transmission to the fetus. In the case of rubella infections, once the prevalence of maternal seroimmunity to rubella virus exceeds approximately 85%, the incidence of congenital rubella infection falls dramatically (Preblud and Alford 1990; MMWR 1997). Thus, the parameters of protective maternal immune responses to viruses such as rubella that do not establish persistent infections in the host or remain endemic in the population appear to differ substantially from those that are necessary to limit congenital CMV infections. It is of interest that aspects of the epidemiology of CMV mirror those seen in congenital syphilis infections, a sexually acquired infection that does not appear to induce protective immunity and whose incidence increases as the prevalence of the infection increases in the population (Anonymous 1999).

Transmission of HCMV to the developing fetus following maternal primary infection occurs in between 20% and 50% of cases (Stagno et al. 1982b; Griffiths and Baboonian 1984; Yow et al. 1988; Stagno and Britt 2006). Because fetal infection occurs in 0.1%-2.0% of women with preconceptional immunity to HCMV, it is clear that maternal immunity plays a major role in protecting the fetus from virus infection (Table 2). However, at what level this host response modulates intrauterine transmission of HCMV and fetal disease is not understood. Recent studies of parameters of HCMV infection and host immunity during primary HCMV infections in pregnancy have described increased levels of viremia and delayed development of CD4+ and CD8+ responses to HCMV that can be correlated with increased rates of fetal infection (Gibson et al. 2007). Although consistent with previous observations that the development of specific adaptive immune responses appeared delayed in primary HCMV infections, the interval between virus acquisition and the development of adaptive immunity in these women cannot be precisely determined (Gibson et al. 2007).

Table 2 Nonprimary maternal HCMV infection and outcome of congenital HCMV infection

Incidence of congenital infection Transmission rate to fetus Incidence of congenitally infected infants with sequelae

Type of maternal infection Primary Non-Primary

Infants with sequelae 31.2 43.5%-69.5

following congenital

HCMV infection"_

a Stagno et al. 1982

b Transmission rates following nonprimary infection varying depending on age and socioeconomic status of population c Fowler et al. 1992

d Rate calculated per 1,000 infants with congenital HCMV infection following primary (130) and nonprimary infection (870)

Finally, a longstanding concept is that maternal immunity to HCMV prior to conception also provides protection to the developing fetus from damaging intra-uterine infection with this virus; however, this protection is far from complete (Stagno et al. 1982b; Stagno and Britt 2006). More recent information suggests that the disease burden secondary to damaging congenital HCMV following nonprimary maternal infection (reactivation of existing infection or reinfection) is significant in delivery populations with an increased seroprevalence (Boppana et al. 1999). Although the frequency of infants with long-lasting sequelae following primary maternal infection is approximately two to three times higher than in infants infected as a result of nonprimary infection, overall in most populations, the incidence of congenitally infected infants born following nonprimary maternal infection is four to five times higher than that following primary maternal infection (Table 2). Thus, the absolute number of infants with long-lasting damage could be nearly the same for both groups (Table 2). These observations have suggested that current vaccine strategies developed for the prevention of neurodevelopmental sequelae associated with congenital HCMV infections that are targeted only at seronegative women may require re-evaluation (Ahlfors et al. 2001; Boppana et al. 2001).

A conventional view is that intrauterine transmission of virus results from viremic spread to the uterine-placental junction, infection of the uterine smooth muscle and endothelial cells, and then placental trophoblasts followed by entry into the fetal blood system (Muhlemann et al. 1992; Sinzger et al. 1993; Ozono et al. 1997; Halwachs-Baumann et al. 1998; Hemmings et al. 1998; Fisher et al. 2000; Pereira et al. 2005) (see the chapter by L. Pereira and E. Maidji, this volume). Histologic examination of placental sections often reveals focal evidence of villitis with evidence of HCMV infection, which would be consistent with this proposed mode of transmission; however, similar observations have been made in placental sections obtained following delivery of normal, uninfected babies. Thus, the host-derived responses that limit intrauterine transmission likely operate at several levels, including systemic responses to HCMV infection and possibly at local sites such as focal infections of the uterus and placenta. Virus-neutralizing antibodies, HCMV-specific CD8+ T lymphocytes, NK cells and resident macrophages could act to prevent virus transmission to the fetus within the infected placenta, although studies supporting such a mechanism are based solely on in vitro activities of these immune effector functions. Interestingly, placental trophoblasts do not express class I HLA-A or HLA- B MHC molecules but do express HLA-G and -E antigens (Kovats et al. 1990; Lanier 1999; Le Bouteiller 2000). The HLA-G molecules have been shown to serve as weak restriction elements for CD8+ T lymphocyte recognition of HCMV-encoded antigenic peptides, but it is unclear if they function similarly in vivo (Lenfant et al. 2003). However, it is also interesting to note that these particular MHC molecules are resistant to degradation induced by the HCMV US2 and US11 gene products and HLA-E can serve to present peptides derived from MHC molecules and presumably viral leader sequences to NK cells (King et al. 1997; Schust et al. 1998, 1999; Lanier 1999; Onno et al. 2000).

More recent findings have demonstrated that membrane-bound forms but not secreted HLA-G can be degraded by US2 (Barel et al. 2003). Decidual NK cells with cytotoxic activity have been described as well as inhibition of their activity by soluble HLA-G (Poehlmann et al. 2006; Tabiasco et al. 2006). These findings point to a complex and dynamic immunological relationship between host, tro-phoblast and virus, and suggest that understanding the role of the placental effector functions could lead to further understanding of how HCMV is transmitted to the developing fetus. Potential routes of transmission to the fetus has been studied in vivo in the guinea pig model of congenital CMV infection (Griffith et al. 1985, 1986). The finding that maternal viremia can be correlated with intrauterine transmission and that passively administered virus neutralizing antibodies could reduce placental infection and intrauterine transmission is consistent with conventional routes of fetal infection (Bourne et al. 2001; Chatterjee et al. 2001). In this model, placental infection has been correlated with both maternal disease and fetal wastage associated with placental infiltration with mononuclear cells (Harrison and Myers 1990; Harrison and Caruso 2000). Thus local inflammatory response secondary to virus infection can occur at the uterine-placental interface, arguing that either viral immune evasion functions or an ineffective host immune response could tip the balance toward fetal infection. Alternatively, the severity of maternal disease seen in the guinea pig model of congenital CMV infection also has raised the very distinct possibility that commonly observed disease manifestations in the guinea pig pup, such as runting, could be related to placental inflammation and insufficiency rather than a direct effect of virus infection on the developing fetal guinea pig. Similar studies have not been accomplished in the mouse model, presumably because of the multilayered structure of the murine placenta limits transplacental transfer of MCMV. Currently, rhesus CMV-free rhesus macaque colonies are being generated and these animals should provide an ideal experimental animal model for investigation of this human infection. Several key questions critical to the pathogenesis of congenital CMV infections remain unanswered, including:

1. What is the relationship between maternal viremia and seeding of the uterus?

2. Is seeding of the placenta associated with cell-free or cell-associated virus?

3. Can resident immune effector functions limit virus infection of the placenta or are circulating mononuclear cells required?

4. Can ascending infections from the uterine cervix infect the fetus?

5. What is the importance of placental inflammation and fetal outcome?

6. How does preexisting maternal immunity limit transmission?

This last question is important for the design of vaccines to limit damaging congenital HCMV infections.

Once the virus has entered the fetal circulation, it can in some instances replicate to high levels and damage a variety of organ systems presumably by lytic replication, although this has not been experimentally verified. Target organs most commonly damaged by severe intrauterine infection include the hepatobiliary system, the central nervous system, the lungs, and hematopoietic system (Becroft 1981;

Boppana et al. 1992, 1997; Perlman and Argyle 1992; Anderson et al. 1996). In almost all cases, infected infants resolve the infection but can be left with sequelae in organ systems with low regenerative capacity such as the brain and auditory system (Boppana et al. 1992, 1997; Dahle 2000). Brain damage and hearing loss can occur in up to 5%-20% of infants with congenital CMV (Fowler et al. 1992; Boppana et al. 1997, 1999; Dahle 2000; Noyola et al. 2001). Hearing loss is the most common long-term sequelae of infants with congenital HCMV infection and in the US and northern Europe may rank second only to familial or genetic causes of hearing loss (Harris et al. 1984; Hicks et al. 1993). Similarly, severe brain damage can result from intrauterine HCMV infection with loss of normal cortical architecture, intracranial calcium deposits following loss of the integrity of the endothelium, and loss of cognitive function (Becroft 1981; Perlman and Argyle 1992; Barkovich and Lindan 1994; Boppana et al. 1997).

Two histopathologic types have been described: a focal infection characterized by microglial nodules and more widespread involvement described as ventriculoencephalitis (Becroft 1981). In the former and more common presentation, virus is assumed to infect the parenchyma of the brain following viremic spread, whereas in infants with more severe disease characterized with ventriculoencephalitis, virus is thought to infect the ventricular epithelium and spread through the periventricular epithelium, possibly through the cerebrospinal fluid (Becroft 1981; Arribas et al. 1996).

The pathogenesis of brain damage following congenital HCMV infection is unknown, but several lines of evidence have suggested that it follows fetal infection early in gestation, and that the symmetry of involvement suggests that it is related to the infection and disruption of the microvasculature of the developing brain and/or disruption of the neuronal migration from the periventricular gray area (Becroft 1981; Perlman and Argyle 1992; Barkovich and Lindan 1994). Mechanisms of cell loss such as virus-induced apoptosis of neuronal stem cells have been suggested based on animal model systems, but only very limited information is available to support this mechanism. At this time, it is unknown whether cell death and/or cell dysfunction is a direct effect of virus infection or secondary to damage to supporting cells and structures from the associated inflammation. Animals models have provided only limited information, and to date, the rhesus macaque fetal model appears to most closely model human disease, although this model requires direct inoculation of the fetus with rhesus CMV (Tarantal et al. 1998). Findings from this model system indicate that gestational age of the fetus at the time of infection appears to determine the extent and severity of disease, a result consistent with the correlation between early gesta-tional maternal seroconversion and central nervous system disease in congenital HCMV infections (Perlman and Argyle 1992; Barkovich and Lindan 1994; Stagno and Britt 2006). Once the fetus is infected, the CMV immune status of the mother appears to have only a limited role in the outcome of the fetal infection. Congenitally infected infants with evidence of end-organ disease and long-term sequelae have higher levels of replicating virus as well as a higher virus burden measured in peripheral blood (Fig. 2) (Stagno et al. 1975; Boppana et al. 2005; Stagno and Britt 2006). Interestingly, the strongest correlation between high viral burden in peripheral blood is the presence of hepatitis and in some infants with severe CNS involvement, the

<100,000 >100,000 genome equivalents in peripheral blood

Fig. 2 Viral load and outcome of congenitally infected infants. DNA was extracted from 200 |il of peripheral blood and analyzed for HCMV viral genomes (reported as genome equivalents/ml) as described. Infants with congenital HCMV infection from a large natural history study of congenital HCMV infection were classified as having long-term neurologic sequelae, and more specifically hearing loss or diminished cognitive function (IQ<70). This study has been reported in more detail (Boppana et al. 2005)

<100,000 >100,000 genome equivalents in peripheral blood

Fig. 2 Viral load and outcome of congenitally infected infants. DNA was extracted from 200 |il of peripheral blood and analyzed for HCMV viral genomes (reported as genome equivalents/ml) as described. Infants with congenital HCMV infection from a large natural history study of congenital HCMV infection were classified as having long-term neurologic sequelae, and more specifically hearing loss or diminished cognitive function (IQ<70). This study has been reported in more detail (Boppana et al. 2005)

viral burden is less than those presenting with only hepatitis (Boppana et al. 2005). This observation can be most readily explained by the duration of the congenital infection such that a predominance of CNS disease can reflect an infection of longer duration with resolution of the hepatic involvement.

Congenitally infected infants can excrete large amounts of virus, often reaching 4-5 logs of infectious virus per milliliter of urine, and can persistently excrete large amounts of virus for years. These same infants can resolve clinical evidence of endorgan disease within the first few months of life even with what is believed to be a limited T lymphocyte response to HCMV (Gehrz et al. 1977; Starr et al. 1979; Pass et al. 1983; Marchant et al. 2003; Gibson et al. 2004). It is of interest, however, that contrary to this previous dogma, newborn infants and fetuses can mount CMV-specific T cell responses, but whether these responses influence outcome of CMV infection in these infants is unknown. Infected infants act as viral reservoirs in their families and communities and serve as an important vector for spreading CMV in populations.

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