Chemoprophylaxis and HIV Host Interactions

 描述（由申请方提供）：使用口服恩布他滨/富马酸替诺福韦酯（FTC/TDF）进行暴露前预防（PrEP），可降低男性同性性行为者和成年异性恋男性和女性的HIV感染率。部分基于由该研究小组领导的iPrEx试验产生的证据，口服FTC/TDF PrEP已获得美国食品和药物管理局的批准，世界卫生组织和美国疾病控制中心已发布其使用建议。随后的iPrEx开放标签扩展（OLE）是第一个PrEP示范项目，以评估与PrEP吸收，PrEP有效使用以及开放标签访问期间的性行为相关的因素。开创性iPrEx研究的所有阶段均于2014年6月完成。这里提出的项目将利用最近完成的iPrEx研究中独特的有价值的标本和数据集合来回答关于HIV暴露者的抗逆转录病毒药物暴露如何减轻感染过程以及通过什么机制的关键未回答的问题。现在有先例表明，早期暴露于抗逆转录病毒药物可以改变感染过程（例如：Visconti队列）或导致病毒缓解延长（例如：密西西比婴儿）。我们发现，在两项PrEP试验（iPrEx和CAPRISA 004）中，与使用PrEP前可检测到的病毒RNA检测相关的前12周PrEP使用中的血清转换在活性组中的频率低于安慰剂组。这种不平衡的趋势在所有PrEP试验中都很明显，这表明在一些达到高浓度抗逆转录病毒药物的人中，新生感染可能会减弱，如口服FTC/TDF给药后的直肠粘膜或使用替诺福韦阴道凝胶后的阴道粘膜。在目标1中，我们将在1000多名开始口服FTC/TDF且从未发生血清转化的iPrEx参与者中寻找艾滋病毒感染失败的证据，即使在PrEP使用间隙期间也是如此。PrEP药物和PrEP使用期间病毒暴露对宿主的影响将通过分析全球宿主基因表达进行探索，该分析最佳地利用了这些试验中具有独特价值的标本。我们将了解如何暴露于PrEP药物可以减少免疫激活的方式，有助于PrEP的保护效益。我们还将了解在缺乏PrEP的情况下，免疫激活和内在抗病毒因子表达的减少是否与随后对HIV感染的易感性有关。这些假设将在目标2中使用最先进的人类转录组的全球评估进行评估，在使用PrEP之前，HIV感染后和抗逆转录病毒暴露后，该项目将利用独特的有价值的iPrEx标本库和数据库来测试直接影响PrEP活性，HIV治愈，持续感染，控制感染易感性的宿主因素的特定假设。

 DESCRIPTION (provided by applicant): Pre-exposure prophylaxis (PrEP) using oral embriticitabine/tenofovir disoproxil fumarate (FTC/TDF) decreases HIV acquisition among men who have sex with men and adult heterosexual men and women. Based in part on evidence generated by the iPrEx trial, led by this team of investigators, oral FTC/TDF PrEP has received approval by the US Food and Drug Administration, and the World Health Organization and the US Centers for Disease Control have issued recommendations for its use. The subsequent iPrEx Open Label Extension (OLE) ecis the first PrEP demonstration project to evaluate factors associated with uptake of PrEP, effective use of PrEP, and sexual practices during open label access. All phases of the pioneering iPrEx studies were completed in June 2014. The project proposed here will leverage the uniquely valuable collections of specimens and data from the recently completed iPrEx studies to answer key unanswered questions about how antiretroviral drug exposure in HIV exposed persons could attenuate the course of infection, and by what mechanisms. There are now precedents that early exposure to antiretroviral drugs can alter the course of infection (eg: the Visconti cohort) or cause prolonged viral remission (eg: the Mississippi infant). We found that seroconversion in the first 12 weeks of PrEP use, associated with detectable viral RNA detection prior to PrEP use, was less frequent in the active arm compared with placebo arm in two PrEP trials (iPrEx and CAPRISA 004). Trends toward this imbalance are evident in all PrEP trials, suggesting that nascent infection may be attenuated in some people who achieve high concentrations of antiretroviral drugs, as might occur in the rectal mucosa after oral FTC/TDF dosing or in the vaginal mucosa after use of a tenofovir vaginal gel. In aim 1, we will seek evidence of aborted HIV infection among more than 1000 iPrEx participants who started oral FTC/TDF and never seroconverted, even during gaps in PrEP use. The impact of PrEP medications, and viral exposure during PrEP use, on the host will be explored using an analysis of global host gene expression that optimally utilizes the uniquely valuable specimens from these trials. We will learn how exposure to PrEP drugs could diminish immune activation in a manner that contributes to PrEP's protective benefit. We will also learn whether diminished immune activation and expression of intrinsic anti-viral factors in the absence of PrEP are associated with subsequent susceptibility to HIV infection. These hypotheses will be evaluated in aim 2 using state-of-the-art global assessment of the human transcriptome at baseline prior to PrEP use, after HIV infection, and after antiretroviral exposure Taken together, this project will leverage the uniquely valuable iPrEx specimen bank and database to test specific hypotheses that bear directly on PrEP activity, HIV cure, persistent infection, host factors governing susceptibility to infection.