Selection for human immunodeficiency virus type 1 envelope glycosylation variants with shorter V1-V2 loop sequences occurs during transmission of certain genetic subtypes and may impact viral RNA levels

Abstract

Designing an effective human immunodeficiency virus type 1 (HIV-1) vaccine will rely on understanding which variants, from among the myriad of circulating HIV-1 strains, are most commonly transmitted and determining whether such variants have an Achilles heel. Here we show that heterosexually acquired subtype A HIV-1 envelopes have signature sequences that include shorter V1-V2 loop sequences and fewer predicted N-linked glycosylation sites relative to the overall population of circulating variants. In contrast, recently transmitted subtype B variants did not, and this was true for cases where the major risk factor was homosexual contact, as well as for cases where it was heterosexual contact. This suggests that selection during HIV-1 transmission may vary depending on the infecting subtype. There was evidence from 23 subtype A-infected women for whom there was longitudinal data that those who were infected with viruses with fewer potential N-linked glycosylation sites in V1-V2 had lower viral set point levels. Thus, our study also suggests that the extent of glycosylation in the infecting virus could impact disease progression.

FIG. 1.

Box plots of V1-V2 length and PNGS for early sequences versus database sequences. Panel A shows the results of subtype A sequence comparisons, and panel B shows the results of subtype B sequence comparisons. The boxes indicated the IQR of the data, and the line within the box represents the median value for each group. The number of sequences in each group is indicated at the bottom. Early sequences are from subjects within 1 year PNS, which was defined as the time from the last HIV-1-negative serological test to when the sample used to obtain sequence was taken. This interval was estimated in the same manner for both subtype A- and subtype B-infected subjects. Thirty-five and 13 subjects contributed to the early sequence subtype A and B data sets, respectively (8, 9, 13, 16). Database-all refers to sequences from the Los Alamos HIV-1 database and includes one randomly selected sequence per subject; sequences know to be within 1 year of infection were excluded from this data set. Database-Kenya refers to sequences from the Los Alamos database that were isolated from Kenyan subjects during chronic infection. The P values for the comparisons between early and database sequences are shown (Wilcoxon rank-sum test; one-sided test). Sequence analyses were confined to the V1-V2 region.

FIG. 2.

Comparison of plasma viral RNA levels at set point to V1-V2 length and PNGS. This comparison was limited to 23 women for whom we had longitudinal viral RNA levels that included a plasma RNA measurement at 4 to 24 months PNS (7). In each of the 23 cases, the viral load measurement was also within a 4- to 24-month period postinfection as defined previously, using both RNA and serology data to more precisely define the time of infection (7). Each point represents the data for one individual. The line representing the linear regression model and the Spearman's correlation coefficient were generated from a data set that excludes one influential point. That influential point is shown with a closed circle.