TOPICAL MICROBICIDE DRUG COMBINATIONS FOR THE PREVENTION OF SHIV

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 艾滋病毒流行病仍在继续，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，没有预防艾滋病毒的疫苗，而且不太可能很快开发出疫苗。这突出表明，迫切需要一个有效的，由女性控制的艾滋病毒预防战略，如阴道应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是无效的，PRO 2000阴道杀微生物剂凝胶的MDP 301 III期试验的令人失望的结果突出表明，用抗逆转录病毒药物配制的凝胶作为保护高风险HIV阴性人群免受感染的潜在生物医学干预措施获得了相当大的关注。这些策略更有希望，因为它们可以提供高剂量的强效药物，可以在粘膜进入点阻断HIV复制。 为此，我们已经成功地制定和评估了几个凝胶含有单一或组合的核苷/核苷酸逆转录酶（恩曲他滨和替诺福韦）或整合酶（雷特格韦）抑制剂。 我们的功效研究表明，使用猪尾猕猴的低剂量、重复SHIV激发模型，单独含有替诺福韦（TFV）或与恩曲他滨（FTC）联合使用的凝胶可以完全预防阴道传播。 此外，评估保护窗口的随访研究表明，TFV提供了持久的保护，并在单次凝胶应用后保留在阴道组织中数天，这表明非性交每日凝胶使用可能不是实现保护所必需的。我们还完成了研究，以评估凝胶与整合酶抑制剂的疗效，并显示他们是高度保护暴露前和暴露后预防，首次证明了这类药物的效用。 这些动物研究通过突出局部抗逆转录病毒预防的高效性推进了该领域，并有助于未来的临床试验设计。

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.