Appreciating HIV type 1 diversity: subtype differences in Env

Abstract

Human immunodeficiency virus type 1 (HIV-1) group M is responsible for the current AIDS pandemic and exhibits exceedingly high levels of viral genetic diversity around the world, necessitating categorization of viruses into distinct lineages, or subtypes. These subtypes can differ by around 35% in the envelope (Env) glycoproteins of the virus, which are displayed on the surface of the virion and are targets for both neutralizing antibody and cell-mediated immune responses. This diversity reflects the remarkable ability of the virus to adapt to selective pressures, the bulk of which is applied by the host immune response, and represents a serious obstacle for developing an effective vaccine with broad coverage. Thus, it is important to understand the underlying biological consequences of intersubtype diversity. Recent studies have revealed that some of the HIV-1 subtypes exhibit phenotypic differences stemming from subtle changes in Env structure, particularly within the highly immunogenic V3 domain, which participates directly in viral entry. This review will therefore explore current research that describes subtype differences in Env at the genetic and phenotypic level, focusing in particular on V3, and highlighting recent discoveries about the unique features of subtype C Env, which is the most globally prevalent subtype.

FIG. 1.

Atomic fluctuations in gp120. Backbone flexibility of the YU2 gp120 molecule was calculated from long time scale equilibrium molecular dynamics simulations. These all atom simulations were carried out with gp120 solvated in explicit solvent molecules. The calculated B-factors correspond to backbone atomic fluctuations and are graphically mapped on an arbitrary structure of a liganded gp120 with modeled loops using a color gradient. The red to blue indicates small to large atomistic fluctuations (rigid to flexible) in the backbone of the structure. The outer domain is relatively more rigid than the inner domain, while the loop regions are also more flexible than the core. Even though the starting conformation of gp120 corresponds to that of the CD4-liganded structure, the CD4 molecule was not included in the calculations. Despite the incomplete sampling of the gp120 conformational space, significant flexibility is observed in the inner domain, some of which is associated with the relief of the conformational constraints induced by binding to CD4.

FIG. 2.

V3 consensus sequences for HIV-1 group M subtypes. Consensus amino acid sequences were obtained from the Los Alamos HIV Database and aligned using Seqpublish. Dashes indicate conserved residues relative to the A1 consensus; dots indicate a deleted residue relative to A1; and amino acid differences from A1 are indicated. The base regions of V3 are underlined. Red residues indicate those participating in a potential “hydrophobic cluster”; green indicates the R/Q substitution that distinguishes B from many non-B subtypes; blue indicates a single difference between the subtype A1 and C consensus.

FIG. 3.

Structure-based analyses of local and global V3 interactions. (A) Contact profile of Ile 309 within the V3 loop. The graph shows the probability of contact plotted on the vertical axis between Ile 309 and the individual residues within V3. The HXB2 amino acid position and the subtype C consensus sequence for V3 are shown on the horizontal axis. The contact profile was obtained from an all-atom molecular dynamics simulation of subtype C consensus gp120 in aqueous solution. The error bars show SEM obtained from 1 ns block analysis. (B) Regions in core gp120 that could potentially interact with Ile 309. A coarse-grained model was used, and residues that showed any contact probability with Ile 309 are mapped onto the gp120 structure (2B4C; in orange). Residues that have been previously shown to participate in CD4 binding are red. The position of Ile 309 at the V3 crown is highlighted in blue.