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Journal of Virology, February 2005, p. 2087-2096, Vol. 79, No. 4
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.4.2087-2096.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Potent Anti-R5 Human Immunodeficiency Virus Type 1 Effects of a CCR5 Antagonist, AK602/ONO4128/GW873140, in a Novel Human Peripheral Blood Mononuclear Cell Nonobese Diabetic-SCID, Interleukin-2 Receptor {gamma}-Chain-Knocked-Out AIDS Mouse Model

Hirotomo Nakata,1 Kenji Maeda,1 Toshikazu Miyakawa,1 Shiro Shibayama,2 Masayoshi Matsuo,2 Yoshikazu Takaoka,2 Mamoru Ito,3 Yoshio Koyanagi,4,{dagger} and Hiroaki Mitsuya1,5*

Department of Infectious Diseases, Kumamoto University Graduate School of Medicine, Kumamoto,1 Ono Pharmaceutical Co. Ltd., Osaka,2 Central Institute for Experimental Animals, Kawasaki,3 Department of Virology, Tohoku University Graduate School of Medicine, Sendai, Japan,4 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland5

Received 27 May 2004/ Accepted 1 October 2004

We established human peripheral blood mononuclear cell (PBMC)-transplanted R5 human immunodeficiency virus type 1 isolate JR-FL (HIV-1JR-FL)-infected, nonobese diabetic-SCID, interleukin 2 receptor {gamma}-chain-knocked-out (NOG) mice, in which massive and systemic HIV-1 infection occurred. The susceptibility of the implanted PBMC to the infectivity and cytopathic effect of R5 HIV-1 appeared to stem from hyperactivation of the PBMC, which rapidly proliferated and expressed high levels of CCR5. When a novel spirodiketopiperazine-containing CCR5 inhibitor, AK602/ONO4128/GW873140 (molecular weight, 614), was administered to the NOG mice 1 day after R5 HIV-1 inoculation, the replication and cytopathic effects of R5 HIV-1 were significantly suppressed. In saline-treated mice (n = 7), the mean human CD4+/CD8+ cell ratio was 0.1 on day 16 after inoculation, while levels in mice (n = 8) administered AK602 had a mean value of 0.92, comparable to levels in uninfected mice (n = 7). The mean number of HIV-RNA copies in plasma in saline-treated mice were ~106/ml on day 16, while levels in AK602-treated mice were 1.27 x 103/ml (P = 0.001). AK602 also significantly suppressed the number of proviral DNA copies and serum p24 levels (P = 0.001). These data suggest that the present NOG mouse system should serve as a small-animal AIDS model and warrant that AK602 be further developed as a potential therapeutic for HIV-1 infection.

* Corresponding author. Mailing address: Department of Infectious Diseases, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Phone: 81-96-373-5156. Fax: 81-96-363-5265. E-mail: hmitsuya{at}helix.nih.gov.

{dagger} Present address: Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.

Journal of Virology, February 2005, p. 2087-2096, Vol. 79, No. 4
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.4.2087-2096.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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