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¹ Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
² AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
³ DNAVEC Research Inc., Tsukuba 305-0856, Japan
⁴ Department of Immunology, Kinki University School of Medicine, Osaka 589-8511, Japan
⁵ Department of Molecular Pathogenesis, Division of Medical Science, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
⁶ Wisconsin Primate Research Center and Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53706
⁷ Toyama Institute of Health, Toyama 939-0363, Japan

Address correspondence to Tetsuro Matano, Department of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Phone: 81-3-5841-3409; Fax: 81-3-5841-3374; email: matano{at}m.u-tokyo.ac.jp

Recently, encouraging AIDS vaccine trials in macaques have implicated cytotoxic T lymphocytes (CTLs) in the control of the simian human immunodeficiency virus SHIV89.6P that induces acute CD4⁺ T cell depletion. However, none of these vaccine regimens have been successful in the containment of replication of the pathogenic simian immunodeficiency viruses (SIVs) that induce chronic disease progression. Indeed, it has remained unclear if vaccine-induced CTL can control SIV replication. Here, we show evidence suggesting that vaccine-induced CTLs control SIVmac239 replication in rhesus macaques. Eight macaques vaccinated with DNA-prime/Gag-expressing Sendai virus vector boost were challenged intravenously with SIVmac239. Five of the vaccinees controlled viral replication and had undetectable plasma viremia after 5 wk of infection. CTLs from all of these five macaques rapidly selected for escape mutations in Gag, indicating that vaccine-induced CTLs successfully contained replication of the challenge virus. Interestingly, analysis of the escape variant selected in three vaccinees that share a major histocompatibility complex class I haplotype revealed that the escape variant virus was at a replicative disadvantage compared with SIVmac239. These findings suggested that the vaccine-induced CTLs had "crippled" the challenge virus. Our results indicate that vaccine induction of highly effective CTLs can result in the containment of replication of a highly pathogenic immunodeficiency virus.

Key Words: CD8⁺ T lymphocytes • selection • MHC • SIV • Sendai virus

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