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Selection of escape mutant by HLA‐C‐restricted HIV‐1 Pol‐specific cytotoxic T lymphocytes carrying strong ability to suppress HIV‐1 replication

2010; Wiley; Volume: 41; Issue: 1 Linguagem: Inglês

10.1002/eji.201040841

1521-4141

Kazutaka Honda, Nan Zheng, Hayato Murakoshi, Masao Hashimoto, Keiko Sakai, Mohamed Ali Borghan, Takayuki Chikata, Madoka Koyanagi, Yoshiko Tamura, Hiroyuki Gatanaga, Shinichi Oka, Masafumi Takiguchi,

HIV/AIDS drug development and treatment

HIV-1 mutants escaping from HLA-A- or HLA-B-restricted CTL have been well studied, but those from HLA-C-restricted CTL have not. Therefore we investigated the ability of HLA-C-restricted CTL to select HIV-1 escape mutants. In the present study, we identified two novel HLA-Cw(*) 1202-restricted Pol-specific CTL epitopes (Pol328-9 and Pol463-10). CTL specific for these epitopes were detected in 25-40% of chronically HIV-1-infected HLA-Cw(*) 1202(+) individuals and had strong abilities to kill HIV-1-infected cells and to suppress HIV-1 replication in vitro, suggesting that these CTL may have the ability to effectively control HIV-1 in some HLA-Cw(*) 1202(+) individuals. Sequence analysis of these epitopes showed that a V-to-A substitution at the 9th position (V9A) of Pol 463-10 was significantly associated with the HLA-Cw(*) 1202 allele and that the V9A mutant was slowly selected in the HLA-Cw(*) 1202(+) individuals. Pol 463-10-specific CTL failed both to kill the V9A virus-infected cells and to suppress replication of the V9A mutant. These results indicate that the V9A mutation was selected as an escape mutant by the Pol463-10-specific CTL. The present study strongly suggests that some HLA-C-restricted CTL have a strong ability to suppress HIV-1 replication so that they can select HIV escape mutants as in the case of HLA-A-restricted or HLA-B-restricted CTL.