Biology Reference
In-Depth Information
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 follow-
ing primary maternal infection is approximately two to three times higher than in
infants infected as a result of nonprimary infection, overall in most popula-
tions, the incidence of congenitally infected infants born following nonprimary
maternal infection is four to five times higher than that following primary mater-
nal 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 particu-
lar 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).
