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。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 2007年，联合国艾滋病规划署报告说，在撒哈拉以南非洲，妇女占成年艾滋病毒/艾滋病感染者的61%。 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艾滋病毒感染。 不幸的是，最近使用非特异性化合物（如硫酸纤维素）作为凝胶的试验在阻断传播方面并不成功。 有效的抗逆转录病毒药物与已知的成功治疗相结合，可能是最有前途的艾滋病毒预防局部策略。 为了实现这一目标，我们已经制定了羟乙基纤维素为基础的凝胶含有两个核苷/核苷酸逆转录酶抑制剂，恩曲他滨（FTC）和替诺福韦（TFV）的组合。 在本研究中，我们使用一种在非人灵长类动物中已确立的重复、低剂量暴露策略，检测FTC/TFV凝胶与安慰剂凝胶相比的疗效。 该研究设计模拟了高风险性暴露于HIV样病毒（称为猿猴/人类免疫缺陷病毒（SHIV））的条件。 我们的研究结果将为FTC/TFV凝胶在预防女性HIV感染中的潜在用途提供急需的临床前指导。 我们已经启动了一项疗效研究，使用重复暴露猕猴模型，每周两次低剂量的SHIV 162 P3阴道激发，共14次激发。 将12只雌性猪尾猕猴分配至安慰剂凝胶组（2%羟乙基纤维素）（n = 6）或5% FTC/1% TFV（溶于2%羟乙基纤维素）凝胶组（n=6）。 在攻击前30分钟将FTC/TFV凝胶或安慰剂凝胶阴道应用于雌性猪尾猕猴，并在攻击前立即收集血液。 每次采血后测定血浆病毒载量和血浆药物水平。

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. In 2007, UNAIDS reported that women comprise 61% of adults in Sub-Saharan Africa living with HIV/AIDS. 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 HIV infection. Unfortunately, recent trials using non-specific compounds (like cellulose sulfate) as gels have not been successful in blocking transmission. Combinations of potent antiretroviral agents with known success as therapy may be the most promising topical strategy for HIV prevention. Towards this goal, we have formulated a hydroxyethylcellulose-based gel containing two nucleoside/nucleotide reverse transcriptase inhibitors, emtricitabine (FTC) and tenofovir (TFV) in combination. In this study, we are testing the efficacy of the FTC/TFV gel as compared to placebo gel using a well-established repeated, low-dose exposure strategy in nonhuman primates. The study design mimics the conditions of high-risk sexual exposure to an HIV-like virus known as Simian/human Immunodeficiency virus (SHIV). Our results will provide much needed preclinical guidance for the potential use of FTC/TFV gel in preventing HIV infection in women. We have initiated an efficacy study using a repeat-exposure macaque model with low dose twice-weekly vaginal challenges with SHIV162P3, for a total of 14 challenges. Twelve female pigtail macaques have been assigned to a placebo gel arm (2% hydroxyethylcellulose) (n = 6) or 5% FTC/1% TFV (in 2% hydroxyethylcellulose) gel arm (n=6). FTC/TFV gel or placebo gel is applied vaginally to female pigtail macaques 30 minutes prior to challenge, and blood is collected immediately prior to challenge. Plasma viral load and plasma drug levels are determined after each blood collection.