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.

The Thai Phase III HIV Type 1 Vaccine Trial (RV144) Regimen Induces Antibodies That Target Conserved Regions Within the V2 Loop of gp120

“…[22][23][24][25][26][27][28] Sequence variation within the V1/V2 loops alters neutralization resistance and viral escape is associated with V2 loop mutations. [29][30][31][32][33] Compared to viruses circulating in chronically infected persons, transmitted viruses (subtypes A and C) appear to have shorter V1/V2 regions and fewer N-linked glycosylation sites. 30,[34][35][36] The V2 loop contains a putative a 4 b 7 integrin binding motif (LDI/V) at amino acid (aa) residues 179-181 (HBX2 numbering system) that was shown to interact with the gut mucosal homing receptor.…”

Donor and Recipient Envs from Heterosexual Human Immunodeficiency Virus Subtype C Transmission Pairs Require High Receptor Levels for Entry

“…Thus, although the majority of subtype C Envs has been shown to use CCR5 and rarely switch to CXCR4 tropism (2,14,18), this is the first study to evaluate the ability of primary subtype C Envs from chronically infected individuals and their acutely infected partners to utilize different levels of receptor and coreceptor. The requirement for high CCR5 levels by subtype C Envs is consistent with reports that infectivity by macrophage-tropic subtype B primary isolates are highly dependent on this coreceptor (20).…”

Maternal Humoral Immune Correlates of Peripartum Transmission of Clade C HIV-1 in the Setting of Peripartum Antiretrovirals

“…While the WITS cohort consisted of clade B HIV-1-infected women from the United States, the BAN cohort of women from Malawi were infected with clade C HIV-1 strains. Interclade amino acid differences in HIV Env glycoproteins can be as high as 35% and influence the genetic selection of different viral strains and their interactions with their host's immune response (14).…”

“…S1 in the supplemental material). Furthermore, studies of V3 among different clades have revealed that the clade C V3 domain is relatively more conserved than that of clade B, as measured by the ratio of nonsynonymous to synonymous substitutions in V3 (14). In addition, the amino acid motifs of a highly conserved turn region of V3 differ between clades B and C (14).…”

“…Furthermore, studies of V3 among different clades have revealed that the clade C V3 domain is relatively more conserved than that of clade B, as measured by the ratio of nonsynonymous to synonymous substitutions in V3 (14). In addition, the amino acid motifs of a highly conserved turn region of V3 differ between clades B and C (14). Clade C appears to be less susceptible to anti-V3-mediated neutralization, suggesting that perhaps clade C V3 is less exposed on the Env trimer (14).…”