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

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.