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and none stain in the placenta. In syncytiotrophoblasts, the neonatal Fc receptor
transcytoses complexes of IgG and virions that potentially infect underlying cytotro-
phoblasts (Maidji et al. 2006). Consistent patterns of replication in cytotrophoblast
progenitors in villi and invasive cells in the decidua suggest that virion receptors are
regulated during development.
Human fibroblasts that support CMV replication express the epidermal growth
factor receptor (EGFR) (Wang et al. 2003) and co-receptors such as integrins αVβ3,
α2β1 and α6β1 (Feire et al. 2004; Wang et al. 2005). In human umbilical vein
endothelial cells (HUVEC), outcomes of infection differ depending on EGFR expres-
sion levels (E. Huang, personal communication). Coordinated signals from high-level
EGFR expression and integrin αVβ3 result in rapid delivery of virion capsids to the
nucleus. Internalization and nuclear transport involve caveolin-mediated endosomal
pathways that are pH independent. Productive infection entails the inhibition of
cofilin phosphorylation and increased tubulin acetylation, which are hallmarks of
actin disassembly and microtubule assembly. Detailed analysis of naturally infected
placentas support strong expression of EGFR and induction of specific integrins as
developmentally induced CMV receptors in cytotrophoblasts that enable intrauterine
replication in sites optimal for virus amplification and fetal transmission.
Villous Cytotrophoblasts Express EGFR
and Upregulate Integrin αV
In naturally infected placentas, CMV replicates in underlying cytotrophoblast pro-
genitors but not in syncytiotrophoblasts covering the villus surface (Fisher et al.
2000; Pereira et al. 2003; Maidji et al. 2007). CMV gB was repeatedly detected in
a punctate staining pattern in syncytiotrophoblasts of immune donors, but viral
replication proteins were absent. Notably, syncytiotrophoblasts expressed EGFR in
apical microvilli, but neither integrin α1β1 nor αV was detected. Occasionally, gB
appeared in a punctate pattern in cytotrophoblast progenitors reactive with antibod-
ies to EGFR and integrin αV, but α1β1 was not detected. Frequently, virion capsids
were found clustered near the microvillous surface of syncytiotrophoblasts, and
CMV DNA was detected by in situ hybridization. These findings indicated that
viral capsids, DNA and gB were present without replication in placentas that con-
tained high-titer neutralizing antibodies, sometimes in the presence of other patho-
gens (McDonagh et al. 2004).
Examination of CMV receptors expressed in cytotrophoblasts of villus
explants infected with a recombinant Toledo rec virus encoding green fluorescent
protein in the villus explant model (Fig. 2a) confirmed that the receptors were
expressed in infected cells. Virions attached in a punctate (green) pattern to apical
microvilli of syncytiotrophoblasts, and some internalized but did not replicate
(Fig. 2b). Although syncytiotrophoblasts express EGFR, functional coreceptors
are missing. Even so, virion-containing immune complexes internalize and colo-
calize with caveolin-1-containing vesicular compartments that were not detected
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