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，对遏制这一流行病至关重要。一个 最佳的杀微生物剂应保护免受感染，而不破坏粘膜环境或其 宿主防御的媒介。本项目的重点是复方杀菌剂的临床前评价 目的是确定安全有效的预防战略。针对至少两种的组合 将优先考虑艾滋病毒生命周期中的各个步骤，从而提供针对循环耐药病毒的保护， 降低药物选择耐药变异的风险。这将通过双 活性的单一抗逆转录病毒药物（ARV），嘧啶二酮，这是一个强大的逆转录酶 抗逆转录病毒抑制剂，并阻止艾滋病毒进入，或通过结合两种不同的抗逆转录病毒杀微生物剂。生物协同作用 艾滋病毒和单纯疱疹病毒之间的关系将通过评估联合使用阿昔洛韦的可能性来解决 与抗逆转录病毒杀微生物剂一起使用，以提供对HSV复制的局部持续抑制。的理由 关注HSV抑制反映了发展中国家中HSV-2的预先存在的高患病率（60-90%）。 世界和压倒性的生物学和流行病学证据表明，亚临床HSV 复发是很常见的，增加了感染艾滋病毒的风险。杀微生物剂方面的重大空白 发展的主要障碍是缺乏可预测安全性和有效性的生物标志物。该项目将解决这些问题 通过开发和扩大新的检测方法，重点是杀微生物剂和 阴道环境，使用原代细胞、外植体培养物和双室培养系统， 鼠模型。所提出的安全性模型关注持续给药对上皮细胞的影响。 完整性和生殖道粘膜免疫。任何观察到的变化的生物学意义将是 通过检查HIV在双重培养中穿过上皮屏障能力的变化来评估 模型和小鼠对生殖器疱疹易感性的变化。从这些研究中获得的结果 将为开发新型安全有效的复合杀微生物剂提供重要信息。

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.