Clinical Control of HIV-1 by Cytotoxic T Cells Specific for Multiple Conserved Epitopes.
Identification and characterization of CD8(+) T cells effectively controlling HIV-1 variants are necessary for the development of AIDS vaccines and for studies of AIDS pathogenesis, although such CD8(+) T cells have been only partially identified. In this study, we sought to identify CD8(+) T cells controlling HIV-1 variants in 401 Japanese individuals chronically infected with HIV-1 subtype B, in which protective alleles HLA-B*57 and HLA-B*27 are very rare, by using comprehensive and exhaustive methods. We identified 13 epitope-specific CD8(+) T cells controlling HIV-1 in Japanese individuals, though 9 of these epitopes were not previously reported. The breadths of the T cell responses to the 13 epitopes were inversely associated with plasma viral load (P = 2.2 × 10(-11)) and positively associated with CD4 count (P = 1.2 × 10(-11)), indicating strong synergistic effects of these T cells on HIV-1 control in vivo. Nine of these epitopes were conserved among HIV-1 subtype B-infected individuals, whereas three out of four nonconserved epitopes were cross-recognized by the specific T cells. These findings indicate that these 12 epitopes are strong candidates for antigens for an AIDS vaccine. The present study highlighted a strategy to identify CD8(+) T cells controlling HIV-1 and demonstrated effective control of HIV-1 by those specific for 12 conserved or cross-reactive epitopes.


OBJECTIVE
HLA-B*27-restricted and HLA-B*57-restricted cytotoxic T lymphocytes (CTLs) play a key role in controlling HIV-1 in Caucasians and Africans, whereas it is unclear which CTLs control HIV-1 in Asian countries, where HLA-B*57 and HLA-B*27 are very rare. A recent study showed that HLA-B*67:01 and HLA-B*52:01-C*12:02 haplotypes were protective alleles in Japanese individuals, but it is unknown whether CTLs restricted by these alleles control HIV-1. In this study, we identified 13 CTLs controlling HIV-1 in Japan by using comprehensive and exhaustive methods. They included 5 HLA-B*52:01-restricted and 3 HLA-B*67:01-restricted CTLs, suggesting that these CTLs play a predominant role in HIV-1 control. The 13 CTLs showed synergistic effects on HIV-1 control. Twelve out of these 13 epitopes were recognized as conserved or cross-recognized ones. These findings strongly suggest that these 12 epitopes are candidates for antigens for AIDS vaccines.
Center for AIDS Research, Kumamoto University, Chuo-ku, Kumamoto, Japan.
Hayato
H
Murakoshi
Center for AIDS Research, Kumamoto University, Chuo-ku, Kumamoto, Japan.
Tomohiro
T
Akahoshi
Center for AIDS Research, Kumamoto University, Chuo-ku, Kumamoto, Japan.
Madoka
M
Koyanagi
Center for AIDS Research, Kumamoto University, Chuo-ku, Kumamoto, Japan.
Takayuki
T
Chikata
Center for AIDS Research, Kumamoto University, Chuo-ku, Kumamoto, Japan.
Takuya
T
Naruto
Center for AIDS Research, Kumamoto University, Chuo-ku, Kumamoto, Japan.
Rie
R
Maruyama
Center for AIDS Research, Kumamoto University, Chuo-ku, Kumamoto, Japan.
Yoshiko
Y
Tamura
Clinical Trial Department, Cancer Institute Hospital, Koto-ku, Tokyo, Japan.
Naoki
N
Ishizuka
Center for AIDS Research, Kumamoto University, Chuo-ku, Kumamoto, Japan AIDS Clinical Center, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan.
Hiroyuki
H
Gatanaga
Center for AIDS Research, Kumamoto University, Chuo-ku, Kumamoto, Japan AIDS Clinical Center, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan.
Shinichi
S
Oka
Center for AIDS Research, Kumamoto University, Chuo-ku, Kumamoto, Japan International Research Center for Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan masafumi@kumamoto-u.ac.jp.
Masafumi
M
Takiguchi
D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology; D044466:Asian People / Q000235:genetics; D018791:CD4 Lymphocyte Count; D017124:Conserved Sequence; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D015488:HIV Antigens / Q000235:genetics; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D016297:Mutagenesis, Site-Directed; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology*; D019562:Viral Load; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte; D015488:HIV Antigens; D015235:HLA-B Antigens; D015796:HLA-B27 Antigen; C103707:HLA-B57 antigen; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D054302:pol Gene Products, Human Immunodeficiency Virus