Chemoprophylaxis and HIV Host Interactions

化学预防和 HIV 宿主相互作用

• 批准号: 9617164
• 负责人: Robert M. Grant
• 金额: $ 32.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9617164
• 关键词: Chemoprophylaxis; HIV; Host; Interactions

 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.

 描述(由申请人提供)：暴露前预防(PrEP)使用口服恩替他滨/替诺福韦富马酸异丙酯(FTC/TDF)可减少与男性发生性关系的男性和成年异性恋男性和女性感染艾滋病毒的机会。在这个调查小组的领导下，部分基于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了使用建议。随后的Iprex开放标签扩展(OLE)ECE是第一个评估与PrEP的摄取、PrEP的有效使用以及开放标签访问期间的性行为相关的因素的PrEP示范项目。开创性的Iprex研究的所有阶段已于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收集，以回答关键的悬而未决的问题，即艾滋病毒感染者接触抗逆转录病毒药物如何减少感染过程，以及通过什么机制。现在有先例表明，早期接触抗逆转录病毒药物可以改变感染过程(例如：Visconi队列)或导致病毒长期缓解(例如：密西西比州婴儿)。在两项PrEP试验(Iprex和CAPRISA 004)中，我们发现，在PrEP使用的前12周，与PrEP使用之前可检测到的病毒RNA检测相关的血清转换，在活动组中比安慰剂组更少发生。这种不平衡的趋势在所有PrEP试验中都很明显，这表明一些获得高浓度抗逆转录病毒药物的人的新生感染可能会得到缓解，就像口服FTC/TDF剂量后的直肠粘膜或使用替诺福韦阴道凝胶后的阴道粘膜一样。在目标1中，我们将在1000多名开始口服FTC/TDF且从未血清转换的Iprex参与者中寻找流产的HIV感染的证据，即使在PrEP使用的间隙也是如此。PrEP药物和PrEP使用期间的病毒暴露对宿主的影响将通过对全球宿主基因表达的分析来探索，该分析最佳地利用了这些试验中独特的有价值的标本。我们将了解暴露在PrEP药物下如何降低免疫活性，从而有助于PrEP的保护作用。我们还将了解，在缺乏PrEP的情况下，免疫活性降低和内在抗病毒因子的表达是否与随后的艾滋病毒感染易感性有关。这些假设将在目标2中进行评估，在PrEP使用之前、艾滋病毒感染后和抗逆转录病毒暴露之后，使用最先进的人类转录组全球评估，该项目将利用独特价值的Iprex标本库和数据库来测试与PrEP活性、艾滋病毒治愈、持续感染、宿主因素控制感染易感性直接相关的特定假设。