Low Postseroconversion CD4+ T-cell Level Is Associated with Faster Disease Progression and Higher Viral Evolutionary Rate in HIV-2 Infection

Abstract

A positive correlation between virus evolutionary rate and disease progression has been shown for human immunodeficiency virus type 1 (HIV-1) infection. Much less is known about HIV-2, the second causative agent of AIDS. We analyzed 528 HIV-2 env V1-C3 sequences generated from longitudinal plasma samples that were collected from 16 study participants during a median observation time of 7.9 years (interquartile range [IQR], 5.2 to 14.0 years). Study participants were classified as faster or slower disease progressors based on longitudinal CD4⁺ T-cell data. The HIV-2 evolutionary rate was significantly associated with CD4⁺ T-cell levels and was almost twice as high among the faster progressors as among the slower progressors. Higher evolutionary rates were accounted for by both synonymous and nonsynonymous nucleotide substitutions. Moreover, slow disease progression was associated with stronger positive selection on HIV-2/SIVsm (simian immunodeficiency virus infecting sooty mangabey) surface-exposed conserved residues. This study demonstrated a number of previously unknown characteristics linking HIV-2 disease progression with virus evolution. Some of these findings distinguish HIV-2 from HIV-1 and may contribute to the understanding of differences in pathogenesis.IMPORTANCE The relationship between HIV evolution and disease progression is fundamental to our understanding of HIV immune control and vaccine design. There are no clear definitions for faster and slower HIV-2 disease progression and for the relationship of the rate of progression with HIV-2 evolution. To address the hypothesis that viral evolution is correlated with disease progression in HIV-2 infection, we determined faster and slower disease progression based on follow-up data from a prospective cohort of police officers in Guinea-Bissau. The analysis showed that although the CD4⁺ T-cell level and the decline in the level were independently associated with progression to AIDS, only the CD4⁺ T-cell level or a combined CD4⁺ T-cell level/decline stratification was associated with the rate of HIV-2 evolution. The HIV-2 evolutionary rate was almost twice as high among the faster progressors as among the slower progressors. Importantly, this report defines previously unknown characteristics linking HIV-2 disease progression with virus evolution.

Keywords: disease progression; human immunodeficiency virus; viral evolution.

FIG 1

Kaplan-Meier curves of AIDS-free time. Three stratifications were explored (fast and slow progressors were defined by having values above or below the mean values from all participants for each stratification). (A) CD4% decline rate. (B) CD4% level at the midpoint in time between the first and last recorded CD4% values. (C) Combined effect of CD4% decline rate and CD4% level. Tick marks indicate participants with censored data. Asterisks indicate the time points in each group when five participants were still at mortality risk and at risk of developing AIDS. The numbers of individuals at risk are given below the figure panels at 5-year intervals. Data from faster progressors are shown in vermillion, and data from slower progressors are shown in blue.

FIG 2

Synonymous and nonsynonymous divergence over time. Data represent accumulated synonymous and nonsynonymous divergences over time in the V1-C3 env region of HIV-2 for each study participant. The divergence from the level seen with the first analyzed sample from each study participant is shown. Data from faster progressors are shown in vermillion, and data from slower progressors are shown in blue.

FIG 3

Codon-specific selective pressure. The selective pressures at each codon site of the sequence alignment of the env V1-C3 region of HIV-2 for faster and slower disease progressors are indicated. The proportions (y axis) with positive selection (vermillion or blue) or negative selection (gray) at codon sites of the sequence alignment (x axis) are shown for faster progressors (upper graph) and slower progressors (lower graph). Filled black circles indicate codons conserved between HIV-2/SIVsm strains associated with positive selection. Vertical lines divide the fragment into env regions V1V2, C2, V3, and C3.