Seki Sayuri, Nomura Takushi, Nishizawa Masako, Yamamoto Hiroyuki, Ishii Hiroshi, Matsuoka Saori, Shiino Teiichiro, Sato Hironori, Mizuta Kazuta, Sakawaki Hiromi, Miura Tomoyuki, Naruse Taeko K, Kimura Akinori, Matano Tetsuro
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Center for AIDS Research, Kumamoto University, Tokyo, Japan.
PLoS Pathog. 2017 Sep 20;13(9):e1006638. doi: 10.1371/journal.ppat.1006638. eCollection 2017 Sep.
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复制施加强大的抑制压力，并选择病毒逃逸突变。其中一些主要组织相容性复合体I类（MHC-I）相关突变导致体外病毒复制能力下降。虽然这些突变在病毒传播到MHC-I不匹配的宿主后可以恢复，但最近的研究表明，这些MHC-I相关突变在人群中积累，使病毒在体外致病性降低。在这里，我们直接表明，在猕猴艾滋病模型中，通过MHC-I不匹配宿主连续传代的MHC-I适应病毒在体内的毒力增加，尽管其体外病毒适应性降低。在具有保护性MHC-I单倍型90 - 120 - Ia的猕猴中，SIVmac239感染1年后获得的第一代猿猴免疫缺陷病毒（1pSIV）被传播到90 - 120 - Ia -猕猴中，感染1年后其血浆被传播到其他90 - 120 - Ia -猕猴中以获得第三代SIV（3pSIV）。在1pSIV中选择的大多数90 - 120 - Ia相关突变即使在3pSIV中也没有恢复。3pSIV显示出较低的体外病毒适应性，但在90 - 120 - Ia -猕猴中诱导持续病毒血症。值得注意的是，与野生型SIVmac239相比，90 - 120 - Ia +猕猴中的3pSIV感染导致病毒载量显著更高且存活率降低。这些结果表明，通过MHC-I不匹配宿主连续传播的MHC-I适应SIVs在MHC-I匹配宿主中可能具有更高的毒力，尽管其体外病毒适应性较低。这项研究表明，多次传代的HIVs可能导致人群中HIV特异性CD8 + T细胞反应丧失，并且这些逃逸病毒的体内致病潜力可能会增强。
