HIV Integrase as a Target for Topical MIcrobicide Development

描述（由申请人提供）：2006年有400多万人新感染艾滋病毒，性传播是全世界主要的感染方式，这突出表明需要制定有效的预防战略。不幸的是，到目前为止，第一代用于阻断性传播的候选局部杀微生物剂的临床试验结果令人失望，因为壬氧醇醚-9 （N-9）和最近的硫酸纤维素（CS）要么不能阻断传播，要么实际上增强了传播。这些结果强调了对高效、安全的杀菌剂候选药物的持续需求。该项目将研究一类新的特异性抗逆转录病毒药物的安全性和有效性，作为局部杀菌剂候选药物，整合酶抑制剂。整合酶抑制剂GS-9160是一种有效的HIV抑制剂，已经在动物和最近的一期人体试验中进行了广泛的研究，并且没有明显的毒性。该药物作为候选杀微生物剂的潜力将分两个阶段进行评估。在R21期，将与吉利德科学合作开发GS-9160的候选凝胶制剂，并评估其体外载药量和稳定性。将在宫颈和阴道上皮细胞单层和宫颈阴道外植体中评估具有良好负载的药物和候选制剂的释放和摄取、细胞毒性和对原代和实验室分离株的有效性。在人类和恒河猴（RM）宫颈阴道外植体中对配制的GS-9160诱导的基因表达进行平行评估，并在R33阶段对体内RM研究中获得的组织和宫颈阴道灌洗液（CVL）进行类似分析，将验证宫颈阴道外植体模型作为体内宿主反应的筛选。如果候选制剂在外植体模型中具有可接受的安全性，如无促炎反应（与N-9相当），并抑制HIV感染，则R33期将开始测试制剂GS-9160阴道给药的局部和全身药代动力学和毒性，然后在阴道感染R5 SHIV的RM中进行疗效研究。拟议的研究将直接解决整合酶抑制剂作为一类是否应该添加到杀微生物剂开发的管道中。此外，拟议的研究将验证生殖器外植体模型作为体内宿主反应的筛选，2006年有超过400万人新感染艾滋病毒，性传播是全球主要的感染方式，突出了有效预防策略的必要性。使用者可以使用局部杀微生物剂来防止艾滋病毒的性传播，但迄今为止在临床试验中表现令人失望。这一建议检验了一种非常有效的抗逆转录病毒药物的局部杀微生物潜力，这种药物可以抑制病毒整合到宿主细胞中。如果在这些研究中取得成功，它将被添加到专门针对艾滋病毒的新一代局部杀微生物剂中。

DESCRIPTION (provided by applicant): Over 4 million individuals were newly infected with HIV in 2006 with sexual transmission the predominant mode of infection worldwide, highlighting the need for effective prevention strategies. Unfortunately clinical trials to date, with the first generation of candidate topical microbicides to block sexual transmission, have been disappointing as both nonoxynol-9 (N-9) and more recently cellulose sulfate (CS) either did not block transmission or actually enhanced transmission. These results highlight the continued need for highly efficacious and safe microbicide candidates. This project will address the safety and efficacy of a new class of specific anti-retrovirals as topical microbicide candidates, integrase inhibitors. The integrase inhibitor, GS-9160, is a potent inhibitor of HIV which has been extensively studied in animals and most recently in a Phase I human trial and has had no significant toxicity. The potential of this drug as a candidate microbicide will be evaluated in two phases. In the R21 phase, a candidate gel formulation of GS-9160 will be generated in collaboration with Gilead Sciences and evaluated for in vitro drug loading and stability. The drug and candidate formulation with favorable loading will be evaluated in cervical and vaginal epithelial cell monolayers and cervicovaginal explants for release and uptake, cytotoxicity and efficacy against primary and laboratory isolates. The parallel evaluation of gene expression induced by formulated GS-9160 in human and rhesus macaque (RM) cervicovaginal explants along with a similar analysis of tissue and cervical vaginal lavage (CVL) fluid derived from in vivo RM studies in the R33 phase will validate the cervicovaginal explant model as a screen for host responses in vivo. If the candidate formulation has an acceptable safety profile as determined by the absence of a proinflammatory response (comparable to N-9) and inhibits HIV infection in the explant model, the R33 phase will be initiated with testing of local and systemic pharmacokinetics and toxicity associated with vaginal delivery of formulated GS-9160 in (RM) followed by an efficacy study in RM vaginally challenged with R5 SHIV. The proposed studies will directly address whether integrase inhibitors as a class should be added to the pipeline for microbicide development. In addition, studies proposed will validate the genital explant model as a screen for host responses in vivo Over 4 million individuals were newly infected with HIV in 2006 with sexual transmission the predominant mode of infection worldwide, highlighting the need for effective prevention strategies. Topical microbicides that could be applied by the user to protect against sexual transmission of HIV have to date been disappointing in clinical trials. This proposal exams the topical microbicide potential of a very potent antiretroviral drug that inhibits integration of the virus into host cells. If successful in these studies it would be added to a new generation of topical microbicides in the pipeline that specifically target HIV.