HIV-1 Envelope Subregion Length Variation during Disease Progression

Abstract

The V3 loop of the HIV-1 Env protein is the primary determinant of viral coreceptor usage, whereas the V1V2 loop region is thought to influence coreceptor binding and participate in shielding of neutralization-sensitive regions of the Env glycoprotein gp120 from antibody responses. The functional properties and antigenicity of V1V2 are influenced by changes in amino acid sequence, sequence length and patterns of N-linked glycosylation. However, how these polymorphisms relate to HIV pathogenesis is not fully understood. We examined 5185 HIV-1 gp120 nucleotide sequence fragments and clinical data from 154 individuals (152 were infected with HIV-1 Subtype B). Sequences were aligned, translated, manually edited and separated into V1V2, C2, V3, C3, V4, C4 and V5 subregions. V1-V5 and subregion lengths were calculated, and potential N-linked glycosylation sites (PNLGS) counted. Loop lengths and PNLGS were examined as a function of time since infection, CD4 count, viral load, and calendar year in cross-sectional and longitudinal analyses. V1V2 length and PNLGS increased significantly through chronic infection before declining in late-stage infection. In cross-sectional analyses, V1V2 length also increased by calendar year between 1984 and 2004 in subjects with early and mid-stage illness. Our observations suggest that there is little selection for loop length at the time of transmission; following infection, HIV-1 adapts to host immune responses through increased V1V2 length and/or addition of carbohydrate moieties at N-linked glycosylation sites. V1V2 shortening during early and late-stage infection may reflect ineffective host immunity. Transmission from donors with chronic illness may have caused the modest increase in V1V2 length observed during the course of the pandemic.

Comparison of Viral Env Proteins from Acute and Chronic Infections with Subtype C Human Immunodeficiency Virus Type 1 Identifies Differences in Glycosylation and CCR5 Utilization and Suggests a New Strategy for Immunogen Design

“…3A). Consistent with the underglycosylation of the Env protein in the transmitted virus, the virus accumulates glycosylation sites during the course of infection (70,78,79). Thus, there appears to be a cycling of glycosylation sites, with a reduction at the time of transmission and an accumulation of sites over time.…”

The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel

“…2D) without affecting the main barrel structure. Interestingly, data have suggested that immune pressure can drive the length of these regions, which may serve as a tool for the virus to evade the immune response (36)(37)(38). However, these SCLs are located at the periphery of the trimer and it is not yet known if they can protect any key sites of Env vulnerability.…”

Longitudinal Analysis of Early HIV-1-Specific Neutralizing Activity in an Elite Neutralizer and in Five Patients Who Developed Cross-Reactive Neutralizing Activity

“…The length and number of PNGS in the V1V2 region of env have been shown to play a crucial role in both autologous and heterologous viral escape (5,6,8,36). In contrast to the normal increase in V1V2 length over the course of infection, the viral variants from the elite neutralizer already had exceptionally long V1V2 regions at the start of infection (72 to 79 amino acids) compared with normal V1V2 length (ϳ65 amino acids) (8) and the length of V1V2 in the other individuals with CrNA (63 to 68 amino acids); these remained long until the last time point before loss to follow-up (47.8 months post-SC), when they declined to an average of 62 amino acids (Fig.…”