HIV-1 infection of trophoblasts is independent of gp120/CD4 Interactions but relies on heparan sulfate proteoglycans.

Mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) is the leading cause of HIV infection in infants. Direct infection of trophoblasts--cells forming the placental barrier--may cause this transmission. Entry of HIV-1 into trophoblasts is unusual for this retrovirus, because it is associated with endocytosis. However, given that trophoblasts express no or few receptors/coreceptors required for virus internalization, the mechanism underlying this event remains ambiguous. In the present study, we show that HIV-1 entry and infection of polarized trophoblasts are independent not only of CD4 but also of envelope (Env) glycoproteins gp120 and gp41. Virus internalization, cytoplasmic release, reverse transcription, integration, and HIV-1 gene expression occurred with both fusion-incompetent and Env-deficient viruses. Importantly, fusion-independent infection was observed when we used viruses produced in a natural cellular reservoir (i.e., primary human cells). Finally, HIV-1 requires heparan sulfate proteoglycans for uptake in trophoblasts. Together, our findings illustrate that HIV-1 utilizes an unusual pathway for entering human polarized trophoblasts.