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.
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.
Nakata
Hirotomo
H
Department of Infectious Diseases, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Maeda
Kenji
K
Miyakawa
Toshikazu
T
Shibayama
Shiro
S
Matsuo
Masayoshi
M
Takaoka
Yoshikazu
Y
Ito
Mamoru
M
Koyanagi
Yoshio
Y
Mitsuya
Hiroaki
H
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D016516:CD4-CD8 Ratio; D004195:Disease Models, Animal; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D010879:Piperazines / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*
C489036:4-((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; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010879:Piperazines; D013141:Spiro Compounds