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 γ-Chain-Knocked-Out AIDS Mouse Model

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Abstract
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 γ-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 ∼10 6 /ml on day 16, while levels in AK602-treated mice were 1.27 × 10 3 /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.