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.

CD8 ⁺ T细胞反应对HIV复制产生强大的抑制压力，并选择病毒逃逸突变。这些主要的组织相容性复杂的I类（MHC-1）相关突变中的某些导致体外病毒复制能力降低。虽然这些突变可以在病毒传播到MHC-1不同的宿主后恢复，但最近的研究表明这些MHC-1相关的突变在人群中积累，使病毒在体外的致病性降低。在这里，我们直接显示了猕猴AIDS模型中通过MHC-I不匹配宿主连续传代通过MHC-I的病毒的体内毒力的增加，尽管在体外减少了病毒健身。第一通道猿猴免疫缺陷病毒（1pSIV）在猕猴获得1年的SIVmac239感染后具有保护MHC-I单倍型90-120-1α被传输到90-120-1α ^-猕猴，其等离子体后1年感染被传送成其它90-120-1α ^-猕猴，以获得第三通道SIV（3pSIV）。在1pSIV中选择的大多数与90-120-Ia相关的突变甚至在3pSIV中也不恢复。3pSIV显示出较低的在体外的病毒适应，但在引起病毒血症90-120-IA ^-猕猴。值得注意的是，在90-120-Ia ^{+中出现了}3pSIV感染与野生型SIVmac239相比，猕猴导致明显更高的病毒载量并降低了存活率。这些结果表明，通过MHC-I不匹配的宿主序列传播的MHC-I适应性SIV在MHC-I匹配的宿主中具有较高的毒力，尽管它们的体外病毒适应性较低。这项研究表明，多次传代的HIV可能会导致人类群体中HIV特异性CD8 ⁺ T细胞反应的丧失，并且这些逃逸病毒的体内致病潜力可能会增强。