HLA-Driven Convergence of HIV-1 Viral Subtypes B and F Toward the Adaptation to Immune Responses in Human Populations

Abstract

BackgroundCytotoxic T-Lymphocyte (CTL) response drives the evolution of HIV-1 at a host-level by selecting HLA-restricted escape mutations. Dissecting the dynamics of these escape mutations at a population-level would help to understand how HLA-mediated selection drives the evolution of HIV-1.Methodology/Principal FindingsWe undertook a study of the dynamics of HIV-1 CTL-escape mutations by analyzing through statistical approaches and phylogenetic methods the viral gene gag sequenced in plasma samples collected between the years 1987 and 2006 from 302 drug-naïve HIV-positive patients. By applying logistic regression models and after performing correction for multiple test, we identified 22 potential CTL-escape mutations (p-value<0.05; q-value<0.2); 10 of these associations were confirmed in samples biologically independent by a Bayesian Markov Chain Monte-Carlo method. Analyzing their prevalence back in time we found that escape mutations that are the consensus residue in samples collected after 2003 have actually significantly increased in time in one of either B or F subtype until becoming the most frequent residue, while dominating the other viral subtype. Their estimated prevalence in the viral subtype they did not dominate was lower than 30% for the majority of samples collected at the end of the 80's. In addition, when screening the entire viral region, we found that the 75% of positions significantly changing in time (p<0.05) were located within known CTL epitopes.ConclusionsAcross HIV Gag protein, the rise of polymorphisms from independent origin during the last twenty years of epidemic in our setting was related to an association with an HLA allele. The fact that these mutations accumulated in one of either B or F subtypes have also dominated the other subtype shows how this selection might be causing a convergence of viral subtypes to variants which are more likely to evade the immune response of the population where they circulate.

Population-Level Immune-Mediated Adaptation in HIV-1 Polymerase during the North American Epidemic

“…Analysis of a European cohort supported the accumulation of HIV-1 adaptations to CTL responses over the period 1985 to 2005 (28), as did a South American study of HIV-1 subtypes B and F over the same time period (29). More strikingly, a recent study of 9 global cohorts revealed a strong positive correlation between the prevalence of HLA-B*51 and that of its associated HIV-1 reverse transcriptase (RT) I135X polymorphism in circulating sequences (22).…”

Efficacy of genotypic drug resistance testing in patients with low-level plasma HIV-1 viremia

“…The PCR conditions were: denaturation for 2 min at 94 8C, primer annealing/elongation: 10 cycles of 15 s at 94 8C, 30 s at 55 8C, 1.5 min at 72 8C followed by 25 cycles of 15 s at 94 8C, 30 s at 55 8C, 1.5 min at 72 8C with addition of 5 s to the elongation time per cycle; final elongation of 7 min at 72 8C. The first round primers are based on the methodology published by Dilernia et al [12]. This methodology and primer sequences were kindly provided by Prof. Richard Harrigan (HIV Centre of Excellence, Vancouver, Canada).…”

Analysis of HIV Type 1 BF Recombinant Sequences from South America Dates the Origin of CRF12_BF to a Recombination Event in the 1970s

“…22 The set of sequence includes the viral gene gag, the viral gene env, and full-length viral genomes as schematized in Fig. 1 23 ).…”