Hierarchy of multiple viral CD8+ T-cell epitope mutations in sequential selection in simian immunodeficiency infection

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 epitopecoding 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. (C) 2022 The Authors. Published by Elsevier Inc.

Automated summary

CD8(+) T-cell responses play an important role in suppressing viral replication and selecting for viral escape mutations in HIV infection. This study investigated the sequential selection of viral mutations in CD8(+) T-cell epitope-coding regions in a simian AIDS model. The results showed that viral mutations were selected in multiple epitope-coding regions, and the number of mutated regions was associated with viral loads.