Inhibition of Human Immunodeficiency Virus Type 1 Infection by the Candidate Microbicide Dapivirine, a Nonnucleoside Reverse Transcriptase Inhibitor
Inhibition of Human Immunodeficiency Virus Type 1 Infection by the Candidate Microbicide Dapivirine, a Nonnucleoside Reverse Transcriptase Inhibitor
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DOI：
10.1128/aac.01156-08
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发表时间：
2009-02-01
影响因子：
4.9
通讯作者：
Shattock, R.
中科院分区：
文献类型：
--
作者：
Fletcher, P.;Harman, S.;Shattock, R.
人类免疫机能丧失病毒（艾滋病毒）的异性性传播仍然是全世界的主要感染途径;因此，迫切需要更多的预防战略，特别是可由妇女控制的战略，例如局部杀微生物剂。潜在的杀微生物剂候选物必须既安全又有效。使用细胞和组织外植体模型，我们已经评估了非核苷类逆转录酶抑制剂（NNRTI）dapivirine作为阴道杀微生物剂的活性。在组织相容性研究中，上皮细胞、T细胞、巨噬细胞和宫颈组织外植体对达匹韦林耐受良好。达匹韦林对来自不同进化枝的一组广泛的HIV 1型分离株表现出强效的剂量依赖性抑制作用。此外，达匹韦林对多种NNRTI耐药分离株表现出强效活性。在人宫颈外植体培养物中，达匹韦林不仅能够抑制粘膜组织的直接感染，还能够防止迁移细胞传播病毒。在精液或宫颈粘液模拟物存在下保留活性。此外，达匹韦林表现出长期抑制作用：它能够预防局部和播散性感染长达6天后处理。生殖器组织预处理后观察到的长期保护作用和缺乏可观察到的毒性表明，达匹韦林作为潜在的杀微生物剂候选物具有相当大的前景。
Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.