Role of Escape Mutant-Specific T Cells in Suppression of HIV-1 Replication and Coevolution with HIV-1

Abstract

The accumulation of HIV-1 escape mutations affects HIV-1 control by HIV-1-specific T cells. Some of these mutations can elicit escape mutant-specific T-cells, but it still remains unclear whether they can suppress the replication of HIV-1 mutant viruses. It is known that HLA-B*52:01-restricted RI8 (Gag 275-282, RMYSPTSI) is a protective T cell epitope in HIV-1 subtype B-infected Japanese individuals, though 3 Gag280A/S/V mutations are found in 26% of them. Gag280S and Gag280A were HLA-B*52:01-associated mutations; whereas Gag280V was not, implying a different mechanism for the accumulation of Gag280 mutations. We here investigated the co-evolution of HIV-1 with RI8-specific T-cells and suppression of HIV-1 replication by its escape mutant-specific T-cells both in vitro and in vivo. The HLA-B*52:01+ individuals infected with Gag280A/S mutant viruses failed to elicit these mutant epitope-specific T-cells, whereas those with the Gag280V mutant one effectively elicited RI8-6V mutant-specific T-cells. These RI8-6V-specific T cells suppressed the replication of Gag280V virus and selected wild-type virus, suggesting a mechanism affording no accumulation of the Gag280V mutation in the HLA-B*52:01+ individuals. The responders to wild-type (RI8-6T) and RI8-6V mutant peptides had significantly higher CD4 counts than non-responders, indicating that the existence of not only RI8-6T-specific T cells but also RI8-6V-specific ones was associated with a good clinical outcome. The present study clarified the role of escape mutant-specific T cells in HIV-1 evolution and in the control of HIV-1. Importance Escape mutant-specific CD8+ T-cells were elicited in some individuals infected with escape mutants, but it is still unknown that these CD8+ T-cells can suppress HIV-1 replication. We clarified that Gag280V mutation were selected by HLA-B*52:01-restricted CD8+ T-cells specific for GagRI8 protective epitope whereas the Gag280V virus could frequently elicit GagRI8-6V mutant-specific CD8+ T-cells. GagRI8-6V mutant-specific T-cells had a strong ability to suppress the replication of the Gag280V mutant virus both in vitro and in vivo. In addition, these T cells contributed to the selection of wild-type virus in HLA-B*52:01+ Japanese individuals. We for the first time demonstrated that escape mutant-specific CD8+ T-cells can suppress HIV-1 replication and play an important role in the coevolution with HIV-1. Thus, the present study highlighted an important role of escape mutant-specific T-cells in the control of HIV-1 and co-evolution with HIV-1.

STING Ligand-Mediated Priming of Functional CD8+T Cells Specific for HIV-1-Protective Epitopes from Naive T Cells

“…4B and Table 2 ). The viral suppression ability of these primed T-cell lines was evaluated by comparing it with that of a positive-control CTL clone, 12B (GagRI8-specific), D3 (PolSI8-specific), or C5 (GagWV8-specific), which showed a very strong viral suppression ability in vitro ( 27 , 34 ). Most of the primed T-cell lines specific for GagRI8, GagWV8, or PolSI8 epitopes exhibited high viral suppression ability, which was approximately 80% of that of the positive-control clone ( Fig.…”

“…Each well contained 200 μl of cell mixture (1 × 10 5 irradiated allogeneic PBMCs from healthy donors and 1 × 10 5 irradiated C1R-B*52:01 cells prepulsed with the peptide at 100 nM, 20 ng/ml of human recombinant interleukin 2 (rIL-2; ProSpec), and 2.5% phytohemagglutinin soup). CTL clones specific for HLA-B*52:01-restricted GagRI8, GagWV8, or PolSI8 were established from HIV-1-infected individuals as previously described ( 27 , 34 ).…”

“…It is therefore expected that CD8 + T cells specific for these protective epitopes may have the ability to eradicate HIV-1-infected cells if they are primed with cGAMP from naive T cells. Our previous studies showed that the HLA-B*52:01-C*12:02 haplotype, which is the most prevalent haplotype in Japanese individuals (approximately 20%), is strongly associated with a good clinical outcome ( 31 ) and demonstrated that 4 HLA-B*52:01-restricted (GagRI8, GagMI8, GagWV8, and PolSI8) and 2 HLA-C*12:02-restricted (PolIY11 and NefMY9) protective and immunodominant cytotoxic T lymphocyte (CTL) epitopes effectively suppress HIV-1 replication both in vitro and in vivo ( 26 , 27 , 32 – 34 ). T cells specific for these protective epitopes may have the ability to eliminate the latent viral reservoir in HIV-1-infected Japanese individuals carrying the HLA-B*52:01-C*12:02 haplotype on cART if the reservoir virus is activated.…”

Functional Profile of CD8+ T-Cells in Response to HLA-A*02:01-Restricted Mutated Epitopes Derived from the Gag Protein of Circulating HIV-1 Strains from Medellín, Colombia

“…Besides, an association between the level of CD8 + T-cell polyfunctionality and the peptide-HLA-I binding affinity was observed; specifically, higher CD8 + T-cell polyfunctionality was found in response to the S54T peptide compared to S54A/E55G peptide, associated with lower HLA-I binding affinity. Some studies have shown that changes at the central position of an epitope may alter its recognition by the T cell receptor (TCR) ( 47 , 48 ) and that the level of polyfunctionality is influenced by the affinity of the TCR-pMHC interaction ( 49 ). Thus, our findings suggest that position six is a relevant site for epitope recognition and that the change from a serine to a threonine may contribute to the avidity of the TCR-pMHC complex.…”

Immunological Control of HIV-1 Disease Progression by Rare Protective HLA Allele

“…A previous study showed that three HLA alleles, HLA-B*67:01, HLA-B*52:01, and HLA-C*12:02, were significantly associated with both low pVL and a high CD4 count in HIV-1 subtype B-infected Japanese individuals, indicating that these three HLA alleles have a protective effect on HIV-1-infected Japanese individuals ( 8 ). Furthermore, it has been demonstrated that the epitope-specific CD8 + T cells restricted by these three protective HLA alleles effectively suppressed HIV-1 replication in Japanese individuals ( 24 – 26 ).…”