Human Cytomegalovirus Infection Interferes with the Maintenance and Differentiation of Trophoblast Progenitor Cells of the Human Placenta

Human cytomegalovirus (HCMV) is amajor cause of birth defects that include severe neurological deficits, hearing and vision loss, and intrauterine growth restriction. Viral infection of the placenta leads to development of avascular villi, edema, andhypoxia associ-atedwith symptomatic congenital infection. Studies of primary cytotrophoblasts (CTBs) revealed thatHCMV infection impedes ter-minal stages of differentiation and invasion by variousmolecularmechanisms.We recently discovered thatHCMVarrests earlier stages involving development of human trophoblast progenitor cells (TBPCs), which give rise to themature cell types of chorionic vil-li—syncytiotrophoblasts on the surfaces of floating villi and invasiveCTBs that remodel the uterine vasculature.Here, we show that viral proteins are present in TBPCs of the chorion in cases of symptomatic congenital infection. In vitro studies revealed thatHCMV replicates in continuously self-renewingTBPC lines derived from the chorion and alters expression and subcellular localization of pro-teins required for cell cycle progression, pluripotency, and early differentiation. In addition, treatmentwith a humanmonoclonal anti-body toHCMVglycoproteinB rescues differentiation capacity, and thus, TBPCs have potential utility for evaluation of the efficacies of novel antiviral antibodies in protecting and restoring placental development.Our results suggest thatHCMVreplicates in TBPCs in the chorion in vivo, interferingwith the earliest steps in the growth of new villi, contributing to virus transmission and impairing com-pensatory development. In cases of congenital infection, reduced responsiveness of the placenta to hypoxia limits the transport of sub