HLA-Associated Clinical Progression Correlates with Epitope Reversion Rates in Early Human Immunodeficiency Virus Infection

Abstract

Human immunodeficiency virus type 1 (HIV-1) can evade immunity shortly after transmission to a new host but the clinical significance of this early viral adaptation in HIV infection is not clear. We present an analysis of sequence variation from a longitudinal cohort study of HIV adaptation in 189 acute seroconverters followed for up to 3 years. We measured the rates of variation within well-defined epitopes to determine associations with the HLA-linked hazard of disease progression. We found early reversion across both the gag and pol genes, with a 10-fold faster rate of escape in gag (2.2 versus 0.27 forward mutations/1,000 amino acid sites). For most epitopes (23/34), variation in the HLA-matched and HLA-unmatched controls was similar. For a minority of epitopes (8/34, and generally associated with HLA class I alleles that confer clinical benefit), new variants appeared early and consistently over the first 3 years of infection. Reversion occurred early at a rate which was HLA-dependent and correlated with the HLA class 1-associated relative hazard of disease progression and death (P ‫؍‬ 0.0008), reinforcing the association between strong cytotoxic T-lymphocyte responses, viral fitness, and disease status. These data provide a comprehensive overview of viral adaptation in the first 3 years of infection. Our findings of HLA-dependent reversion suggest that costs are borne by some escape variants which may benefit the host, a finding contrary to a simple immune evasion paradigm. These epitopes, which are both strongly and frequently recognized, and for which escape involves a high cost to the virus, have the potential to optimize vaccine design.

Demographic Processes Affect HIV-1 Evolution in Primary Infection before the Onset of Selective Processes

“…We found more examples of mutations to rare amino acids than to conserved amino acids, suggesting more escape than reversions. Conflicting reports about the relative prevalence of reversions in early HIV-1 infection have been published (16,21,26,32,33,39,45). The large number of reversions found in earlier studies may have been due to the experimental methods, i.e., using (i) consensus sequencing (39), (ii) a cross-sectional cohort (45), or (iii) HXB2 or another unrelated sequence as a reference to score reversions (rather than a baseline sequence) (16).…”

“…Conflicting reports about the relative prevalence of reversions in early HIV-1 infection have been published (16,21,26,32,33,39,45). The large number of reversions found in earlier studies may have been due to the experimental methods, i.e., using (i) consensus sequencing (39), (ii) a cross-sectional cohort (45), or (iii) HXB2 or another unrelated sequence as a reference to score reversions (rather than a baseline sequence) (16). In our study, we analyzed the database frequency of mutations relative to that of the consensus sequence at the first time point, using a perhaps stringent criterion for assigning the direction of mutations: a 50% decrease/increase in database frequency for forward/reverse mutations (the reference database consists of independent circulating HIV-1 subtype B sequences from the Los Alamos National Laboratory HIV database [HIVDB]).…”

Fluidity of HIV-1-Specific T-Cell Responses during Acute and Early Subtype C HIV-1 Infection and Associations with Early Disease Progression

“…These data provide insight into the contribution of CTL in the resolution of acute-phase viremia. There is also strong inferential evidence supporting HLA class 1-driven viral evolution across the HIV-1 genome in both subtype B and C HIV infection (4,9,14,23,44,50,53), where a high density of HLA-associated mutation sites can be found in Nef relative to Pol, Gag, and other regulatory proteins, suggesting that CTL recognition exerts differential selection pressures in selected regions (9,44,53). This also may explain the high proportion of lost responses in Nef relative to Gag, Pol, and Env that we observed.…”

Influence of Gag-Protease-Mediated Replication Capacity on Disease Progression in Individuals Recently Infected with HIV-1 Subtype C

“…Further, although the host expressed the alleles to select these polymorphisms, it is unlikely that many were selected by the host at such an early stage of infection and that they were largely inherited. Usually, in the Gag protein, the fastest selection occurs in epitopes restricted by the protective HLA-B*57/5801 within about 6 months of infection (7, 18) (but on average at 13 months postinfection according to another study [11]), and reversion events rather than selection of new mutations in Gag predominate in early infection (11,14). Further, Schaefer et al showed that in linked transmission pairs most of the HLA-associated polymorphisms present at 1 year after infection were transmitted and not selected by the host (39), and it is estimated that approximately 18% of the possible mutations in Gag are present in transmitted viruses on average (20).…”