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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.

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 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 approximately 10(6)/ml on day 16, while levels in AK602-treated mice were 1.27 x 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.
AuthorsHirotomo Nakata, Kenji Maeda, Toshikazu Miyakawa, Shiro Shibayama, Masayoshi Matsuo, Yoshikazu Takaoka, Mamoru Ito, Yoshio Koyanagi, Hiroaki Mitsuya
JournalJournal of virology (J Virol) Vol. 79 Issue 4 Pg. 2087-96 (Feb 2005) ISSN: 0022-538X [Print] United States
PMID15681411 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 4-((4-((3R)-1-butyl-3-((1R)) cyclohexylhy-droxymethyl)-2,5-dioxo-1,4,9-triazaspiro(5.5)undec-9-yl methyl)phenoxy)benzoic acid hydrochloride
  • Anti-HIV Agents
  • CCR5 Receptor Antagonists
  • Piperazines
  • Spiro Compounds
Topics
  • Animals
  • Anti-HIV Agents (chemical synthesis, chemistry, metabolism, pharmacology)
  • CCR5 Receptor Antagonists
  • CD4-CD8 Ratio
  • Disease Models, Animal
  • HIV Infections (immunology, virology)
  • HIV-1 (drug effects, physiology)
  • Humans
  • Leukocytes, Mononuclear (drug effects, virology)
  • Mice
  • Mice, SCID
  • Piperazines (pharmacology)
  • Spiro Compounds (pharmacology)

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