Driving HIV-1 into a Vulnerable Corner by Taking Advantage of Viral Adaptation and Evolution

Abstract

Anti-retroviral therapy (ART) is crucial for controlling human immunodeficiency virus type-1 (HIV-1) infection. Recently, progress in identifying and characterizing highly potent broadly neutralizing antibodies has provided valuable templates for HIV-1 therapy and vaccine design. Nevertheless, HIV-1, like many RNA viruses, exhibits genetically diverse populations known as quasispecies. Evolution of quasispecies can occur rapidly in response to selective pressures, such as that exerted by ART and the immune system. Hence, rapid viral evolution leading to drug resistance and/or immune evasion is a significant barrier to the development of effective HIV-1 treatments and vaccines. Here, we describe our recent investigations into evolutionary pressure exerted by anti-retroviral drugs and monoclonal neutralizing antibodies (NAbs) on HIV-1 envelope sequences. We also discuss sensitivities of HIV-1 escape mutants to maraviroc, a CCR5 inhibitor, and HIV-1 sensitized to NAbs by small-molecule CD4-mimetic compounds. These studies help to develop an understanding of viral evolution and escape from both anti-retroviral drugs and the immune system, and also provide fundamental insights into the combined use of NAbs and entry inhibitors. These findings of the adaptation and evolution of HIV in response to drug and immune pressure will inform the development of more effective antiviral therapeutic strategies.

Keywords: HIV-1; antiretroviral therapy; escape; evolution; neutralizing antibody.

FIGURE 1

Human immunodeficiency virus type-1 (HIV-1) Env. (A) Entry of HIV-1 into a host cell involves interactions between the Env and the two-receptor mechanism of CD4 and the coreceptor. (B) Tertiary schematic view of HIV-1 Env. Following the binding of CD4 and gp120, gp120 undergoes conformational changes, moving from a rigid (unliganded) to a flexible state, allowing a subsequent interaction with the coreceptors. bNAbs have been identified that target the V2 apex, the V3 high-mannose patch, the CD4bs, the gp120/41 interface, the FP, and the MPER of gp41. In the CD4-bound state, a larger area is uncovered and potentially available for recognition by NAbs, such as V3-directed or CD4i, which recognize the conserved coreceptor-binding site. (C) Linear schematic view of HIV-1 Env. Gp120 is composed of five conserved regions (C1 to C5) that are interspersed with five variable regions (V1 to V5).

FIGURE 2

Schematic view of the relationship between NAb resistance and CCR5 inhibitor resistance (A), and the function of CD4mc (B). (A) Selection pressures on HIV-1 Env by NAbs and/or CCR5 inhibitors might turn the tide in the fight against HIV-1. The relationship indicates that NAbs and CCR5 inhibitors may restrict the emergence of variants that are resistant to each other. (B) CD4mc is a bifunctional entry inhibitor. The use of bifunctional entry inhibitors that display direct blockade of viral entry and exposure of epitopes to NAbs, should be effective in passive NAb immunization.