HIV: cell binding and entry

Abstract

The first step of the human immunodeficiency virus (HIV) replication cycle-binding and entry into the host cell-plays a major role in determining viral tropism and the ability of HIV to degrade the human immune system. HIV uses a complex series of steps to deliver its genome into the host cell cytoplasm while simultaneously evading the host immune response. To infect cells, the HIV protein envelope (Env) binds to the primary cellular receptor CD4 and then to a cellular coreceptor. This sequential binding triggers fusion of the viral and host cell membranes, initiating infection. Revealing the mechanism of HIV entry has profound implications for viral tropism, transmission, pathogenesis, and therapeutic intervention. Here, we provide an overview into the mechanism of HIV entry, provide historical context to key discoveries, discuss recent advances, and speculate on future directions in the field.

Figure 1.

Overview of HIV entry. To deliver the viral payload into cells, HIV Env, comprised of gp120 and gp41 subunits (1), first attaches to the host cell, binding CD4 (2). This causes conformational changes in Env, allowing coreceptor binding, which is mediated in part by the V3 loop of Env (3). This initiates the membrane fusion process as the fusion peptide of gp41 inserts into the target membrane, followed by six-helix bundle formation and complete membrane fusion (4).

Figure 2.

Model of gp120 engagement of CD4 and CXCR4. Recent structural studies have enhanced our understanding of the molecular interactions between gp120 (cyan) and its receptors. Here, CD4 (green) and CXCR4 (purple), shown as monomers for clarity, are shown simultaneously binding to gp120. (A) Lateral view. (B) Top view. However, the number of CD4 and coreceptor molecules required to interact with Env to mediate productive fusion remains unknown. (C) Gp120 has two key interactions with coreceptor. (1) The base of the V3 loop binds to the amino-terminal domain of the coreceptor, whereas the tip of the V3 loop binds to the second extracellular loop (ECL2). Although both interactions are important, viral strains differ on their dependency of each interaction. (Structural model generated by Wu et al. 2010.)

Figure 3.

Model of DC-mediated transinfection of CD4⁺ T cells. (A) DCs capture and concentrate virions in trypsin-resistant surface-accessible compartments. (B) CD4⁺ T cells, containing membrane protrusions, bind DCs. (C) The CD4⁺ T-cell protrusions invade the virus-containing compartments and efficiently bind HIV. (D) Virus then migrates toward the cell body to initiate infection. (Figure reproduced from Felts et al. 2010; reprinted, with permission, from Proceedings of the National Academy of Sciences © 2010.)