TOPICAL MICROBICIDE DRUG COMBINATIONS FOR THE PREVENTION OF SHIV

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 艾滋病毒大流行仍在继续，估计每天有13,000名新感染者，其中绝大多数是通过异性性行为感染的。目前，还没有预防艾滋病毒的疫苗，而且不太可能很快开发出一种疫苗。这突显了迫切需要一种有效的、由女性控制的艾滋病毒预防战略，例如经阴道使用的杀微生物剂凝胶，使妇女能够保护自己免受传播。由于第一代杀微生物剂已被证明无效，PRO 2000阴道杀微生物剂凝胶的MDP 301第三阶段试验结果令人失望，用抗逆转录病毒药物配制的凝胶作为一种潜在的生物医学干预措施受到了相当大的关注，以保护高危HIV阴性者免受感染。这些策略更有希望，因为它们可以提供大剂量的有效药物，可以在粘膜入口点阻止艾滋病毒复制。 为此，我们已经成功地配制并评价了几种含有核苷/核苷酸逆转录酶(恩曲他滨和替诺福韦)或整合酶(雷替格列韦)抑制剂单一或组合的凝胶。我们的疗效研究表明，含有替诺福韦(TFV)的凝胶或与恩曲他滨(FTC)联合使用，可以通过低剂量、重复的SHV攻击模型在尾辫猕猴身上完全预防阴道传播。此外，评估保护窗口的后续研究表明，TFV提供了长期的保护，并在单次使用凝胶后在阴道组织中保留数天，这表明可能没有必要使用非性交日常使用凝胶来实现保护。我们还完成了评估含有整合酶抑制剂的凝胶的有效性的研究，并表明它们对暴露前和暴露后的预防都具有高度保护作用，首次展示了这类药物的实用性。 这些动物研究突出了局部抗逆转录病毒预防的高效性，并有助于未来的临床试验设计，从而推动了该领域的发展。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The HIV pandemic continues with an estimated 13,000 new infections each day, the vast majority acquired through heterosexual sex. Currently, no vaccine is available to prevent HIV and it is unlikely that one will be developed soon. This highlights the critical need for an effective, female-controlled HIV prevention strategy such as a vaginally-applied microbicide gel, which can enable women to protect themselves from transmission. Because first generation microbicides have been proved ineffective, highlighted by the disappointing results from the MDP 301 Phase III trial of PRO 2000 vaginal microbicide gel, gels formulated with antiretroviral drugs has gained considerable attention as a potential biomedical intervention to protect high-risk HIV-negative people from becoming infected. These strategies are more promising because they can deliver a high dose of potent drugs that can block HIV replication at the mucosal point of entry. To this end, we have successfully formulated and evaluated several gels containing single or combinations of nucleoside/nucleotide reverse transcriptase (emtricitabine and tenofovir) or integrase (Raltegravir) inhibitors. Our efficacy studies show that gels containing tenofovir (TFV) alone or in combination with emtricitabine (FTC) can fully protect against vaginal transmission using a low-dose, repeat SHIV challenge model in pigtailed macaques. In addition, follow-up studies evaluating the window of protection showed that TFV provided long-lasting protection and remained in vaginal tissues for days following a single gel application, suggesting that non-coital daily gel use may not be necessary to achieve protection. We also completed studies to assess the efficacy of gels with integrase inhibitors and show them to be highly protective for both pre- and post exposure prophylaxis, demonstrating for the first time the utility of this class of drugs. These animal studies advance the field by highlighting the high efficacy of topical antiretroviral prophylaxis and aid in future clinical trial designs.