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. Although 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.

Figure 1

HIV Env-mediated membrane fusion and its inhibition. Key steps of HIV fusion following the engagement of CD4 and coreceptor by the gp120 subunit of Env glycoprotein are illustrated. The gp41 subunit refolds from its native conformation through a series of pre-bundle structures that expose conserved heptad repeat domains (shown as red and blue cylinders) into the post-fusion 6-helix bundle structure. Peptides derived from the C-terminal heptad repeat domain of gp41 (dark blue) bind to the complementary N-terminal domains (red) and prevent the formation of helical bundles. The dashed arrow between a hemifused state and the peptide-trapped intermediate is intended to show that this intermediate, and even nascent fusion pores, can be reversed in the presence of the peptides.

Figure 2

Alternative HIV entry routes into a cell and experimental strategies to define the point of entry. (A) Sequential steps of hemifusion and fusion and redistribution of the viral membrane and content markers are illustrated for the HIV entry at the cell surface and through endocytosis. Virions that do not engage a requisite number of CD4 and coreceptors are degraded (dashed arrows). The pseudocolor transformation schemes corresponding to these pathways are shown above and on the right side of the cartoon. (B) Kinetic measurements of HIV fusion by adding a peptide inhibitor of gp41 6-helix bundles, dynamin inhibitor (dynasore) or by lowering the temperature (temperature block, TB) at indicated time points (arrows). If fusion occurs at the cell surface, the kinetics of escape from all three inhibitors should be similar (illustrated for the TB experiments by a dashed line).

Figure 3

A model for regulation of the HIV entry sites. HIV fusion with endosomes may be augmented by cellular factors (not shown) that help enlarge the pore. Whereas fusion with the plasma membrane does not normally progress beyond hemifusion, conditions that allow for lateral force generation (red dotted arrows) by cells, in this case, virus being bound to two adjacent cells, are conducive to force generation and can thus allow virus-cell or cell-cell fusion (“fusion from without”). The events that were experimentally observed by single virus imaging [46] are shown by solid black arrows and those hypothesized to occur between two cells are shown by dashed blue arrows.