In vivo virulence of MHC-adapted AIDS virus serially-passaged through MHC-mismatched hosts

Cd8+t-cell responses exert strong suppressive pressure on hiv replication and select for viral escape mutations. some of these major histocompatibility complex class i (mhc-i)-associated mutations result in reduction of in vitro viral replicative capacity. while these mutations can revert after viral transmission to mhc-i-disparate hosts,recent studies have suggested that these mhc-i-associated mutations accumulate in populations and make viruses less pathogenic in vitro. here,we directly show an increase in the in vivo virulence of an mhc-i-adapted virus serially-passaged through mhc-i-mismatched hosts in a macaque aids model despite a reduction in in vitro viral fitness. the first passage simian immunodeficiency virus (1psiv) obtained 1 year after sivmac239 infection in a macaque possessing a protective mhc-i haplotype 90-120-ia was transmitted into 90-120-ia-macaques,whose plasma 1 year post-infection was transmitted into other 90-120-ia-macaques to obtain the third passage siv (3psiv). most of the 90-120-ia-associated mutations selected in 1psiv did not revert even in 3psiv. 3psiv showed lower in vitro viral fitness but induced persistent viremia in 90-120-ia-macaques. remarkably,3psiv infection in 90-120-ia+macaques resulted in significantly higher viral loads and reduced survival compared to wild-type sivmac239. these results indicate that mhc-i-adapted sivs serially-transmitted through mhc-i-mismatched hosts can have higher virulence in mhc-i-matched hosts despite their lower in vitro viral fitness. this study suggests that multiply-passaged hivs could result in loss of hiv-specific cd8+t cell responses in human populations and the in vivo pathogenic potential of these escaped viruses may be enhanced. © 2017 seki et al.