Impact of HLA-B*52:01-Driven Escape Mutations on Viral Replicative Capacity

Abstract

HLA-B*52:01 is strongly associated with protection against HIV disease progression. However, the mechanisms of HLA-B*52:01-mediated immune control have not been well studied. We here describe a cohort with a majority of HIV C-clade-infected individuals from Delhi, India, where HLA-B*52:01 is highly prevalent (phenotypic frequency, 22.5%). Consistent with studies of other cohorts, expression of HLA-B*52:01 was associated with high absolute CD4 counts and therefore a lack of HIV disease progression. We here examined the impact of HLA-B*52:01-associated viral polymorphisms within the immunodominant C clade Gag epitope RMTSPVSI (here, RI8; Gag residues 275 to 282) on viral replicative capacity (VRC) since HLA-mediated reduction in VRC is a central mechanism implicated in HLA-associated control of HIV. We observed in HLA-B*52:01-positive individuals a higher frequency of V280T, V280S, and V280A variants within RI8 (P = 0.0001). Each of these variants reduced viral replicative capacity in C clade viruses, particularly the V280A variant (P < 0.0001 in both the C clade consensus and in the Indian study cohort consensus p24 Gag backbone), which was also associated with significantly higher absolute CD4 counts in the donors (median, 941.5 cells/mm3; P = 0.004). A second HLA-B*52:01-associated mutation, K286R, flanking HLA-B*52:01-RI8, was also analyzed. Although selected in HLA-B*52:01-positive subjects often in combination with the V280X variants, this mutation did not act as a compensatory mutant but, indeed, further reduced VRC. These data are therefore consistent with previous work showing that HLA-B molecules that are associated with immune control of HIV principally target conserved epitopes within the capsid protein, escape from which results in a significant reduction in VRC. IMPORTANCE Few studies have addressed the mechanisms of immune control in HIV-infected subjects in India, where an estimated 2.7 million people are living with HIV. We focus here on a study cohort in Delhi on one of the most prevalent HLA-B alleles, HLA-B*52:01, present in 22.5% of infected individuals. HLA-B*52:01 has consistently been shown in other cohorts to be associated with protection against HIV disease progression, but studies have been limited by the low prevalence of this allele in North America and Europe. Among the C-clade-infected individuals, we show that HLA-B*52:01 is the most protective of all the HLA-B alleles expressed in the Indian cohort and is associated with the highest absolute CD4 counts. Further, we show that the mechanism by which HLA-B*52:01 mediates immune protection is, at least in part, related to the inability of HIV to evade the HLA-B*52:01-restricted p24 Gag-specific CD8+ T-cell response without incurring a significant loss to viral replicative capacity.

Effect of Difference in Consensus Sequence between HIV-1 Subtype A/E and Subtype B Viruses on Elicitation of Gag-Specific CD8+T Cells and Accumulation of HLA-Associated Escape Mutations

“…The consensus sequence of Gag280 in the HIV-1 subtype C virus was Val. A recent study demonstrated a reduced viral replication capacity of the subtype C virus having a GagV280T/S/A mutation as compared with that of the consensus-type subtype C virus (33). This present study also showed no significant difference in viral-replication capacity between the subtype B virus (NL4-3)…”

Definition of a New HLA B*52-Restricted Rev CTL Epitope Targeted by an HIV-1-Infected Controller

“…While there is sequence variation within the epitope, the P2 and P8 anchor positions are highly conserved ( Tables S3 and S4 ) [ 19 ]. HLA-B*52 has been associated with resistance to HIV-1-infection [ 20 ], with early control after infection [ 16 ] and with non-progression to AIDS [ 21 , 22 , 23 , 24 , 25 ]. So far, it has been speculated that this beneficial effect of HLA-B*52 is mediated by CTL selecting escape mutations within HLA B*52-restricted Gag- and Pol-epitopes leading to decreased viral replicative capacity [ 22 , 26 ].…”

“…HLA-B*52 has been associated with resistance to HIV-1-infection [ 20 ], with early control after infection [ 16 ] and with non-progression to AIDS [ 21 , 22 , 23 , 24 , 25 ]. So far, it has been speculated that this beneficial effect of HLA-B*52 is mediated by CTL selecting escape mutations within HLA B*52-restricted Gag- and Pol-epitopes leading to decreased viral replicative capacity [ 22 , 26 ]. Here, we report on the delineation of the Rev-RI8 peptide as a new HLA-B*52-restricted CTL epitope in Rev.…”

Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes

“…The modest polymorphism observed for topologically important epitopes that precludes them from being classified as exact matches in HIV-1 M group is likely the result of their underlying immunogenicity, which we observed in this study. Moreover, mutations within highly networked epitopes have been shown to impair viral fitness, so these responses may be effective in mediating immune control despite mutational changes [ 26 , [59] , [60] , [61] ]. The finding that the Network epitopes display some sequence variation and were targeted more robustly than the Epigraph peptides could indicate that these are more immunogenic in vivo and that these topologically important regions would indeed be part of the peptide repertoire presented on infected target cells.…”