This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nakata, H. Articles by Mitsuya, H. Search for Related Content PubMed PubMed Citation Articles by Nakata, H. Articles by Mitsuya, H.

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 -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, and Hiroaki Mitsuya^1,5*

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-1_JR-FL)-infected, nonobese diabetic-SCID, interleukin 2 receptor -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.

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

This article has been cited by other articles:

• Nakata, H., Steinberg, S. M., Koh, Y., Maeda, K., Takaoka, Y., Tamamura, H., Fujii, N., Mitsuya, H. (2008). Potent Synergistic Anti-Human Immunodeficiency Virus (HIV) Effects Using Combinations of the CCR5 Inhibitor Aplaviroc with Other Anti-HIV Drugs. Antimicrob. Agents Chemother. 52: 2111-2119 [Abstract] [Full Text]  
• Kondru, R., Zhang, J., Ji, C., Mirzadegan, T., Rotstein, D., Sankuratri, S., Dioszegi, M. (2008). Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists. Mol. Pharmacol. 73: 789-800 [Abstract] [Full Text]  
• Nakata, H., Amano, M., Koh, Y., Kodama, E., Yang, G., Bailey, C. M., Kohgo, S., Hayakawa, H., Matsuoka, M., Anderson, K. S., Cheng, Y.-C., Mitsuya, H. (2007). Activity against Human Immunodeficiency Virus Type 1, Intracellular Metabolism, and Effects on Human DNA Polymerases of 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine. Antimicrob. Agents Chemother. 51: 2701-2708 [Abstract] [Full Text]  
• Watanabe, S., Terashima, K., Ohta, S., Horibata, S., Yajima, M., Shiozawa, Y., Dewan, M. Z., Yu, Z., Ito, M., Morio, T., Shimizu, N., Honda, M., Yamamoto, N. (2007). Hematopoietic stem cell-engrafted NOD/SCID/IL2R{gamma}null mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses. Blood 109: 212-218 [Abstract] [Full Text]  
• Miyazato, P., Yasunaga, J.-i., Taniguchi, Y., Koyanagi, Y., Mitsuya, H., Matsuoka, M. (2006). De Novo Human T-Cell Leukemia Virus Type 1 Infection of Human Lymphocytes in NOD-SCID, Common {gamma}-Chain Knockout Mice. J. Virol. 80: 10683-10691 [Abstract] [Full Text]  
• Baenziger, S., Tussiwand, R., Schlaepfer, E., Mazzucchelli, L., Heikenwalder, M., Kurrer, M. O., Behnke, S., Frey, J., Oxenius, A., Joller, H., Aguzzi, A., Manz, M. G., Speck, R. F. (2006). Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2-/-{gamma}c-/- mice. Proc. Natl. Acad. Sci. USA 103: 15951-15956 [Abstract] [Full Text]  
• Maeda, K., Das, D., Ogata-Aoki, H., Nakata, H., Miyakawa, T., Tojo, Y., Norman, R., Takaoka, Y., Ding, J., Arnold, G. F., Arnold, E., Mitsuya, H. (2006). Structural and Molecular Interactions of CCR5 Inhibitors with CCR5. J. Biol. Chem. 281: 12688-12698 [Abstract] [Full Text]  
• Nishikawa, M., Takashima, K., Nishi, T., Furuta, R. A., Kanzaki, N., Yamamoto, Y., Fujisawa, J.-i. (2005). Analysis of Binding Sites for the New Small-Molecule CCR5 Antagonist TAK-220 on Human CCR5. Antimicrob. Agents Chemother. 49: 4708-4715 [Abstract] [Full Text]