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CD8 + T-cell responses exert strong suppressive pressure on viral replication and select for viral escape mutations in HIV infection. Multiple viral epitopes restricted by major histocompatibility complex class I (MHC-I) are targeted by CD8 + T cells. Sequential selection of viral escape mutations in individual epitope-coding regions could result in failure in CD8 + T cell-based viral control leading to disease progression. However, how this sequential selection of epitope mutations occurs has not fully been determined. Here, we examined sequential selection of viral mutations in seven CD8 + T-cell epitope-coding regions in a macaque AIDS model of simian immunodeficiency virus mac239 (SIVmac239) infection. In seven SIVmac239-infected Burmese rhesus macaques possessing MHC-I haplotype 90-120-Ia, selection of viral mutations was observed in five to seven of the seven 90-120-Ia-associated CD8 + T-cell epitope-coding regions in a year post-infection. Of the seven CD8 + T-cell epitopes, viral mutation selection was detected first at two epitopes, Gag 206-216 and Nef 9-19 , but was found finally at Vif 114-124 epitope in most animals. Viral loads in 6 months were significantly associated with the number of mutated CD8 + T-cell epitope-coding regions 1 year post-infection. Tetramer analysis revealed early induction of Gag 241-249 specific CD8 + T-cell responses, which did not always result in early selection of viral mutations in the Gag 241-249 epitope, suggesting that the order of epitope mutation selection may not be determined only by immunodominance. This SIV infection model using 90-120-Ia-positive macaques would be useful for analysis of the determinants for sequential epitope mutation selection, contributing to our understanding of virus-host CD8 + T-cell interaction in HIV infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Cumulative studies on human immunodeficiency virus (HIV)-infected individuals have shown association of major histocompatibility complex class I (MHC-I) polymorphisms with lower viral load and delayed AIDS progression, suggesting that HIV replication can be controlled by potent CD8 + T-cell responses. We have previously established an AIDS model of simian immunodeficiency virus (SIV) infection in Burmese rhesus macaques and found a potent CD8 + T cell targeting the Mamu-A1*065:01-restricted Gag 241-249 epitope, which is located in a region corresponding to the HIV Gag 240-249 TW10 epitope restricted by a protective MHC-I allele, HLA-B*57. In the present study, we determined a T cell receptor (TCR) of this Gag 241-249 epitope-specific CD8 + T cell. cDNA clones encoding TCR-α and TCR-β chains were obtained from a Gag 241-249 -specific CD8 + T-cell clone. Coexpression of these TCR-α and TCR-β cDNAs resulted in reconstitution of a functional TCR specifically detected by Gag 241-249 epitope-Mamu-A1*065:01 tetramer. Two of three previously-reported CD8 + T-cell escape mutations reduced binding affinity of Gag 241-249 peptide to Mamu-A1*065:01 but the remaining one not. This is consistent with the data obtained by molecular modeling of the epitope-MHC-I complex and TCR. These results would contribute to understanding how viral CD8 + T-cell escape mutations are selected under structural constraint of viral proteins., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections, host major histocompatibility complex class I (MHC-I) genotypes have a great impact on viral replication and MHC-I-associated viral genome mutations are selected under CD8 + T-cell pressure. Association of MHC-I genotypes with HIV/SIV control has been investigated at MHC-I allele levels but not fully at haplotype levels. We previously established groups of rhesus macaques sharing individual MHC-I haplotypes. In the present study, we compared viral genome diversification after SIV infection in macaques possessing a protective MHC-I haplotype, 90-010-Id, with those possessing a non-protective MHC-I haplotype, 90-010-Ie. These two MHC-I haplotypes are associated with immunodominant CD8 + T-cell responses targeting similar regions of viral Nef antigen. Analyses of viral genome sequences and antigen-specific T-cell responses showed four and two candidates of viral CD8 + T-cell targets associated with 90-010-Id and 90-010-Ie, respectively, in addition to the Nef targets. In these CD8 + T-cell target regions, higher numbers of mutations were detected at the setpoint after SIV infection in macaques possessing 90-010-Id than those possessing 90-010-Ie. These results indicate higher selective pressure on overall CD8 + T-cell targets associated with the protective MHC-I haplotype, suggesting a pattern of HIV/SIV control by multiple target-specific CD8 + T-cell responses., (Copyright © 2019 Elsevier Inc. All rights reserved.)