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

Escape mutant-specific CD8+ T cells were elicited in some individuals infected with escape mutants, but it is still unknown whether 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 the 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 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 mutants. It is known that HLA-B*52:01-restricted RI8 (Gag 275 to 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. In this study, we investigated the coevolution 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. 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 nonresponders, 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 whether 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 the 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 coevolution with HIV-1.

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