HIV entry: a game of hide-and-fuse?

Abstract

Human Immunodeficiency Virus (HIV) initiates infection by fusing its envelope membrane with the cell membrane through a process which is triggered through interactions with the cellular receptor and coreceptor. While the mechanism of HIV fusion has been extensively studied, the point of its entry into cells remains controversial. HIV has long been thought to fuse directly with the cell plasma membrane. However, several lines of evidence suggest that endocytic entry of HIV can lead to infection and, moreover, that endocytosis could be the predominant HIV entry pathway into different cell types. This review discusses recent findings pertinent to HIV entry routes and novel approaches to pinpoint the sites of virus entry.

Cholesterol-Dependent Membrane Fusion Induced by the gp41 Membrane-Proximal External Region–Transmembrane Domain Connection Suggests a Mechanism for Broad HIV-1 Neutralization

“…Thus, plasma membrane-virus fusion would be arrested at a hemifusion stage, while progression to fusion pore formation and dilation would require assistance by endosome-resident factors. According to such a mechanism, the lipid protrusion activity of the MPER-TMD connection would evolve in the context of the cell surface and would therefore be accessible to blocking factors from the external medium (68). The observation that the functional 4E10 antibody could halt the CpreTM-induced fusion process would be compatible with this possibility (Fig.…”

Distinct Requirements for HIV-Cell Fusion and HIV-mediated Cell-Cell Fusion

“…Although the mechanism of Env-mediated fusion is reasonably well understood (1)(2)(3), the sites of HIV-1 entry into cells remain controversial (4,5). The widely held view that HIV-1 directly fuses with the plasma membrane (6 -11) has been challenged by several studies showing pH-independent endocytic entry of this virus into different cell types, including primary macrophages (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

“…HIV-1 envelope glycoprotein (Env) 4 initiates the release of the nucleocapsid into the cytosol by fusing the viral membrane with the host cell membrane, a process that is initiated upon the sequential binding of Env to CD4 and coreceptors, CXCR4 or CCR5. The assembly of ternary Env-CD4-coreceptor complexes triggers refolding of the transmembrane gp41 subunit into the final 6-helix bundle structure, which ultimately leads to the merger of viral and cellular membranes.…”

Resolving the Sites of HIV Entry: Dynamin Networks Hold the Key

“…This has immediately been interpreted as a confirmation that HIV is dependent on endocytosis for completion of fusion and subsequent infection [48]. An alternate interpretation is that small molecule inhibitors can block HIV events that are not related to endocytosis.…”

“…The literature has established polarised models of HIV fusion site entry that are either entirely at the plasma membrane or entirely within endosomes [26,27,48]. Other investigators have tried to bridge these two polarised camps by proposing a model which addresses a continuum of HIV fusion sites.…”