Terrazas-Aranda Katty, Van Herrewege Yven, Hazuda Daria, Lewi Paul, Costi Roberta, Di Santo Roberto, Cara Andrea, Vanham Guido
Virology Unit, Department of Microbiology, Institute of Tropical Medicine, Nationalestraat 155, B-2000 Antwerpen, Belgium.
Antimicrob Agents Chemother. 2008 Jul;52(7):2544-54. doi: 10.1128/AAC.01627-07. Epub 2008 May 12.
Conceptually, blocking human immunodeficiency virus type 1 (HIV-1) integration is the last possibility for preventing irreversible cellular infection. Using cocultures of monocyte-derived dendritic cells and CD4(+) T cells, which represent primary targets in sexual transmission, we demonstrated that blocking integration with integrase strand transfer inhibitors (InSTIs), particularly L-870812, could consistently block cell-free and cell-associated HIV-1 infection. In a pretreatment setting in which the compound was present before and during infection and was afterwards gradually diluted during the culture period, the naphthyridine carboxamide L-870812 blocked infection with the cell-free and cell-associated HIV-1 Ba-L strain at concentrations of, respectively, 1,000 and 10,000 nM. The potency of L-870812 was similar to that of the nucleotide reverse transcriptase inhibitor R-9-(2-phosphonylmethoxypropyl) adenine (PMPA) but one or two orders of magnitude lower than those of the nonnucleoside reverse transcriptase inhibitors UC781 and TMC120. In contrast, the diketo acid RDS derivative InSTIs showed clear-cut but weaker antiviral activity than L-870812. Moreover, L-870812 completely blocked subtype C and CRFO2_AG primary isolates, which are prevalent in the African heterosexual epidemic. Furthermore, the addition of micromolar concentrations of L-870812 even 24 h after infection could still block both cell-free and cell-associated Ba-L, opening the prospect of postexposure prophylaxis. Finally, an evaluation of the combined activity of L-870812 with either T20, zidovudine, PMPA, UC781, or TMC120 against replication-deficient HIV-1 Ba-L (env) pseudovirus suggested synergistic activity for all combinations. Importantly, compounds selected for the study by using the coculture model were devoid of acute or delayed cytotoxic effects at HIV-blocking concentrations. Therefore, these findings provide evidence supporting consideration of HIV-1 integration as a target for microbicide development.
从概念上讲，阻断1型人类免疫缺陷病毒（HIV-1）整合是预防不可逆细胞感染的最后一种可能。利用单核细胞衍生的树突状细胞和CD4(+) T细胞的共培养物（它们是性传播中的主要靶细胞），我们证明用整合酶链转移抑制剂（InSTIs），特别是L-870812阻断整合，能够持续阻断无细胞和细胞相关的HIV-1感染。在一种预处理情况下，即在感染前和感染期间存在该化合物，然后在培养期间逐渐稀释，萘啶羧酰胺L-870812分别在1000和10000 nM的浓度下阻断无细胞和细胞相关的HIV-1 Ba-L株感染。L-870812的效力与核苷酸逆转录酶抑制剂R-9-(2-膦酰甲氧基丙基)腺嘌呤（PMPA）相似，但比非核苷逆转录酶抑制剂UC781和TMC120低一到两个数量级。相比之下，二酮酸RDS衍生物InSTIs显示出明确但比L-870812弱的抗病毒活性。此外，L-870812完全阻断了在非洲异性传播流行中普遍存在的C亚型和CRFO2_AG原始分离株。此外，即使在感染后24小时加入微摩尔浓度的L-870812仍能阻断无细胞和细胞相关的Ba-L，这为暴露后预防带来了希望。最后，对L-870812与T20、齐多夫定、PMPA、UC781或TMC120联合对复制缺陷型HIV-1 Ba-L（env）假病毒的活性评估表明，所有组合均有协同活性。重要的是，通过共培养模型选择用于该研究的化合物在HIV阻断浓度下没有急性或延迟的细胞毒性作用。因此，这些发现提供了证据支持将HIV-1整合作为杀微生物剂开发的靶点。
