Curlin ME, Zioni R, Hawes SE, Liu Y, Deng W, Gottlieb GS, Zhu T, Mullins JI (2010). HIV-1 envelope subregion length variation during disease progression. PLoS pathogens, 6(12), e1001228. (pubmed) (doi)
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.
- Figure 1 (pdf), black and white. Schematic diagram of HIV-1 env subregions (center bar) and distribution of subregion loop lengths (surrounding bar graphs). The center bar depicts the linear arrangement of subregions V1V2 through V5 within the HIV Env gp120 protein. The amino acid length distribution of each subregion is shown in the linked bar graphs, including sequences in the cross-sectional dataset, the longitudinal dataset and the transmission data described in the supplementary analyses. Length distributions in V1V2 and V4 data are shown by isolation site and subtype. X-axis: sequence length (amino acids); Y-axis: number of sequences.
- Supplental Table 1 (xls) V1V2 gene sequence data and associated clinical and demographic data contributing to longitudinal, cross-sectional and transmission analyses. Data unavailable to the authors at the time of analysis are listed as “u/k”. For additional information or data on other gene regions, please contact the authors.