Abstract
BackgroundDespite the low level of viral replication in HIV controllers (HICs), studies have reported viral mutations related to escape from cytotoxic T-lymphocyte (CTL) response in HIV-1 plasma sequences. Thus, evaluating the dynamics of the emergence of CTL-escape mutants in HICs reservoirs is important for understanding viremia control. To analyze the HIV-1 mutational profile and dynamics of CTL-escape mutants in HICs, we selected 11 long-term non-progressor individuals and divided them into the following groups: (1) viremic controllers (VCs; n = 5) and (2) elite controllers (ECs; n = 6). For each individual, we used HIV-1 proviral DNA from PBMCs related to earliest (VE) and latest (VL) visits to obtain gag and nef sequences using the Illumina HiSeq system. The consensus of each mapped gene was used to assess viral divergence, and next-generation sequencing data were employed to identify SNPs and variations within and flanking CTL epitopes.ResultsDivergence analysis showed higher values for nef compared to gag among the HICs. EC and VC groups showed similar divergence rates for both genes. Analysis of the number of SNPs showed that VCs present more variability in both genes. Synonymous/non-synonymous mutation ratios were < 1 for gag among ECs and for nef among ECs and VCs, exhibiting a predominance of non-synonymous mutations. Such mutations were observed in regions encoding CTL-restricted epitopes in all individuals. All ECs presented non-synonymous mutations in CTL epitopes but generally at low frequency (< 1%); all VCs showed a high number of mutations, with significant frequency changes between VE and VL visits. A higher frequency of internal mutations was observed for gag epitopes, with significant changes across visits compared to Nef epitopes, indicating a pattern associated with differential genetic pressure.ConclusionsThe high genetic conservation of HIV-1 gag and nef among ECs indicates that the higher level of viremia control restricts the evolution of both genes. Although viral replication levels in HICs are low or undetectable, all individuals exhibited CTL epitope mutations in proviral gag and nef variants, indicating that potential CTL escape mutants are present in HIC reservoirs and that situations leading to a disequilibrium of the host-virus relationship can result in the spread of CTL-escape variants.
Highlights
Despite the low level of viral replication in HIV controllers (HICs), studies have reported viral mutations related to escape from cytotoxic T-lymphocyte (CTL) response in HIV-1 plasma sequences
Study subjects A cohort of 11 HICs with an longterm non-progressors (LTNPs) profile, defined as subjects infected with HIV-1 for at least eight years and maintaining RNA viral loads lower than 2000 copies/ml and CD4+ T cells counts higher than 500 cells/mm3 without antiretroviral treatment (ART), were followed-up at the Instituto Nacional de Infectologia Evandro Chagas (INI), Rio de Janeiro, Brazil
These subjects were classified into the following groups according to plasma viral load (VL): (1) elite controllers (ECs) if most (≥ 70%) plasma viral load determinations were below the limit of detection for clinically available assays (< 50 or < 80 copies/ml) (n = 6) and (2) viremic controllers (VCs) if most (≥ 70%) VL determinations were between 80 and 2000 copies/ml (n = 5)
Summary
Despite the low level of viral replication in HIV controllers (HICs), studies have reported viral mutations related to escape from cytotoxic T-lymphocyte (CTL) response in HIV-1 plasma sequences. In addition to variants that show escape from neutralizing antibodies [12], CTL-escape mutations are important to HIV-1 pathogenesis, as much evidence points to the pivotal role of the CD8+ T cell response in viral control [13,14,15,16] and as a continuous force driving viral selection [17]. These escape mutations have been characterized as amino acid changes occurring in central (impairing TCR recognition) and terminal (modifying anchor residues) regions of CTL epitopes or in their flanking regions, impairing epitope processing [18]. In individuals with protective HLA alleles, like HLA B*57 and B*27, those mutations arise faster in higher numbers [26] and preferentially, at anchor residues or multisite [27]
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