HIV‐1 Infection of Trophoblasts Is Independent of gp120/CD4 Interactions but Relies on Heparan Sulfate Proteoglycans

Abstract

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.

Siglecs Facilitate HIV-1 Infection of Macrophages through Adhesion with Viral Sialic Acids

“…The involvement of carbohydrate recognition in HIV-1 infection has been controversial largely due to the use of cell lines in early research discoveries [34], [35]. This is also supported by the known antiviral effects of many carbohydrate binding agents (CBA), such as bacterial cyanovirin-N (CVN) and some plant lectins [36].…”

Human Mucosal Mast Cells Capture HIV-1 and Mediate Viral trans -Infection of CD4 + T Cells

“…infection (1,8,32,33,(38)(39)(40)(41)(42). The administration of an anti-␣4␤7 monoclonal antibody reduced mucosal transmission of simian immunodeficiency virus (SIV) in macaques (43).…”

Different Regions of HIV-1 Subtype CenvAre Associated with Placental Localization andIn UteroMother-to-Child Transmission

“…Paradoxically, it has also been reported that syncytiotrophoblast express either a low level of CD4 or CCR5 molecules or none (18,44), although this finding is inconsistent (14,50). Trophoblasts are known to express various C-type lectins, like gelatins, DC SIGN, globoside, and syndecans, on their surfaces (12,33,34), many of which can serve as attachment receptors for HIV-1 in CD4-negative cell lines (8,20,28,45,80). Because env V1 length and glycosylation are important in several aspects of the viral life cycle, including replication competence (76), tropism (9,26), and cytopathology (37,55,76), it is possible that the observed differences in env V1 loop lengths between peripheral and placental compartments in cases of in utero transmission are a manifestation of placental adaptation, such as an increased adherence to C-type lectins.…”