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

PLoS Pathogens

Saori Matsuoka¹  Teiichiro Shiino¹  Hiroyuki Yamamoto¹  Takushi Nomura¹  Sayuri Seki¹  Hiroshi Ishii¹  Hironori Sato¹  Masako Nishizawa²  Taeko K. Naruse³  Tomoyuki Miura³  Hiromi Sakawaki³  Tetsuro Matano⁴  Akinori Kimura⁴  Kazuta Mizuta⁵ 

[1] AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan;Center for AIDS Research, Kumamoto University, Tokyo, Japan;Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan;Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan;Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan

关键词: Macaque;    SIV;    T cells;    Cytotoxic T cells;    Microbial mutation;    Viral load;    Haplotypes;    HIV;   

DOI  :  10.1371/journal.ppat.1006638

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY