Efficacy & Safety of Multitargeted Combination Microbicides to Prevent HIV & HSV

局部杀微生物剂是一种由女性控制的预防艾滋病毒的战略，在遏制这一流行病方面至关重要。一个 理想的杀微生物剂应在不破坏粘膜环境或其功能的情况下防止感染 东道主辩护的调解人。本项目的重点是联合杀菌剂的临床前评估。 目的是确定安全有效的预防战略。至少针对两个目标的组合 将优先考虑艾滋病毒生命周期中的步骤，从而提供保护，防止传播耐药病毒和 降低药物选择耐药变种的风险。这将通过DUAL 一种有效逆转录酶的单一抗逆转录病毒药物(ARV)--嘧啶二酮的活性 抑制剂，还可以阻止艾滋病毒进入，或通过联合使用两种不同的抗逆转录病毒微生物剂。生物协同效应 将通过评估联合应用阿昔洛韦的可能性来解决艾滋病毒和单纯疱疹病毒之间的关系 用ARV杀微生物剂提供局部持续的HSV复制抑制。其基本原理是 关注HSV抑制反映了以前存在的HSV-2在发展中国家的高流行率(60%-90%) 世界和压倒性的生物学和流行病学证据表明亚临床单纯疱疹病毒 复发是相当常见的，增加了感染艾滋病毒的风险。杀菌剂的关键差距 发展是缺乏预测安全性和有效性的生物标记物。该项目将解决这些问题 通过开发和扩大新的分析方法来缩小差距，这些方法的重点是杀菌剂和 阴道环境，使用原代细胞、外植体培养和双室培养系统 小鼠模型。所提出的安全性模型侧重于持续给药对上皮细胞的影响。 完整性与生殖道粘膜免疫。任何观察到的变化的生物学意义都将是 通过检测HIV在双重培养中穿越上皮屏障的能力的变化来评估 模型和小鼠对生殖器疱疹易感性的变化。从这些研究获得的结果 将为新型安全有效的复合杀菌剂的发展提供关键信息。

Topical microbicides, a female-controlled strategy to prevent HIV, are crucial in stemming the pandemic. An optimal microbicide should protect against infection without disrupting the mucosal environment or its mediators of host defense. This project focuses on the preclinical evaluation of combination microbicides with the goal of identifying safe and effective prevention strategies. Combinations that target at least two steps in the HIV life cycle will be prioritized, thus providing protection against circulating resistant viruses and reducing the risk that the drugs will select for resistant variants. This will be accomplished through the dual activities of a single antiretroviral drug (ARV), a pyrimidinedione, which is a potent reverse transcriptase inhibitor and also blocks HIV entry, or by combining two different ARV microbicides. The biological synergy between HIV and HSV will be addressed by evaluating the possibility of delivering acyclovir in combination with the ARV microbicides to provide local sustained suppression of HSV replication. The rationale for focusing on HSV suppression reflects the pre-existing high prevalence of HSV-2 (60-90%) in the developing world and the overwhelming biological and epidemiological evidence demonstrating that subclinical HSV recurrences, which are quite common, increase the risk for HIV acquisition. Critical gaps in microbicide development are the lack of biomarkers predictive of safety and efficacy. This project will address these gaps by developing and expanding novel assays, which focus on the interactions between microbicides and the vaginal environment, using primary cells, explant cultures, and a dual chamber culture system and murine models. The proposed safety models focus on the impact of sustained drug delivery on epithelial integrity and genital tract mucosal immunity. The biological significance of any observed changes will be assessed by examining changes in the ability of HIV to traverse the epithelial barrier in the dual culture model and changes in the susceptibility to genital herpes in the mouse. Results obtained from these studies will provide crucial information for the advancement of novel safe and effective combination microbicides.