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
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
复制标题
DOI：
10.1128/jvi.79.4.2087-2096.2005
复制
发表时间：
2005-02-01
影响因子：
5.4
通讯作者：
Mitsuya, H
中科院分区：
文献类型：
--
作者：
Nakata, H;Maeda, K;Mitsuya, H
我们建立了人外周血单个核细胞（PBMC）移植的R5人类免疫缺陷病毒1型分离株JR-FL（HIV-1（JR-FL））感染，非肥胖糖尿病-SCID，白细胞介素2受体T链敲除（NOG）小鼠，其中发生了大量和系统性的HIV-1感染。植入的PBMC对R5 HIV-1的感染性和细胞病变效应的易感性似乎源于PBMC的超活化，其快速增殖并表达高水平的CCR 5。当一种新的含螺二酮哌嗪的CCR 5抑制剂AK 602/ONO 4128/GW 873140（分子量，614）在接种R5 HIV-1后1天给予NOG小鼠时，R5 HIV-1的复制和细胞病变效应被显著抑制。在生理盐水处理的小鼠（n = 7）中，接种后第16天的平均人CD 4（+）/CD 8（+）细胞比率为0.1，而给予AK 602的小鼠（n = 8）的水平平均值为0.92，与未感染小鼠（n = 7）的水平相当。在第16天，生理盐水处理的小鼠血浆中HIV-RNA的平均拷贝数与10（6）/ml相似，而AK 602处理的小鼠血浆中HIV-RNA的平均拷贝数为1.27 × 10（3）/ml（P = 0.001）。AK 602还显著抑制前病毒DNA拷贝数和血清p24水平（P = 0.001）。这些数据表明，目前的NOG小鼠系统应作为一个小动物艾滋病模型，并保证AK 602被进一步开发为一个潜在的治疗HIV-1感染。
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 T-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 similar to10(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.