Potent anti-R5 human immunodeficiency virus type 1 effects of a CCR5 antagonist, AK602/ONO4128/GW873140, in a novel human peripheral blood mononuclear cell …

H Nakata, K Maeda, T Miyakawa, S Shibayama… - Journal of …, 2005 - Am Soc Microbiol
H Nakata, K Maeda, T Miyakawa, S Shibayama, M Matsuo, Y Takaoka, M Ito, Y Koyanagi…
Journal of virology, 2005Am Soc Microbiol
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 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 …
Abstract
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 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 ∼106/ml on day 16, while levels in AK602-treated mice were 1.27 × 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.
American Society for Microbiology