Chemoprophylaxis and HIV-Host Interactions

描述（由申请人提供）：联合国艾滋病规划署估计，尽管人们普遍知道禁欲、减少伴侣数量和使用避孕套的保护作用，但每天仍有14000例新的HIV-1感染发生。没有已知的候选疫苗或局部杀微生物剂具有保护作用，密集的咨询也不足以完全阻止传播。预防艾滋病毒的新方法需要紧急评估。这是一个项目的竞争性延续申请，旨在了解每日口服抗病毒药物对血清阴性患者HIV-1预防的病毒学和免疫学意义。自24个月前启动以来，该项目在国际化学预防研究组合中发挥了重要作用，支持对血清转化物的耐药性进行深入评估，并储存病毒学、免疫学和药理学分析所需的标本。与以前一样，该项目的科学目的是检验这样一种假设，即与安慰剂相比，化学预防可能具有持续的益处（或风险），其持续时间超过化学预防治疗的时间，包括由于在全身感染之前长期暴露于病毒抗原而可能产生的免疫反应（目标2a）得以保存，因此在进行化学预防治疗的患者中感染过程的衰减（目标1）（目标3a）。那些尽管持续高水平暴露于HIV-1（尽管有咨询），但血清阴性的人可能会出现hiv特异性细胞介导或体液免疫反应，更大的自然杀伤细胞活性，或保护性宿主限制因子的表达（目的2b），这可能是由抗病毒药物所含的病毒暴露引起的（目的3b）。我们还将确定耐药感染是否在化学预防暴露期间更常见，以及耐药病毒是否随着时间的推移甚至在化学预防停止后占主导地位，这对耐药变异的二次传播具有影响。使用抗病毒药物与安慰剂的预防试验提供了独特的机会来研究病毒和宿主之间的相互作用，这种相互作用是传播的基础，血浆病毒RNA设定点的建立，以及暴露后的宿主保护。本研究旨在阐明化学预防成功或失败的机制，这对于预测长期利益（和风险）以及设计下一代化学预防试验至关重要。

DESCRIPTION (provided by applicant): UNAIDS estimates that 14,000 new HIV-1 infections occur every day despite widespread knowledge of the protective effects of abstinence, reductions in partners, and and condom use. No vaccine candidates or topical microbicides are known to be protective, and intensive counseling was not sufficient to stop transmission completely. Novel approaches to HIV prevention warrant urgent evaluation. This is a competing continuation application for a project that aimed to understand the virological and immunological implications of daily oral antiviral use for HIV-1 prevention in seronegative persons. Since its inception 24 months ago, the project has developed an important role in the international portfolio of chemoprophylaxis research, by supporting the intensive evaluation of seroconverters for drug resistance and the storage of specimens required for virological, immunological, and pharmacological analysis. As before, the scientific aims aims of the project are to test the hypothesis that chemoprophylaxis may have durable benefits (or risks), compared with placebo, that extend beyond the period of chemoprophylactic treatment, including attenuation of the course of infection among those who become infected despite chemoprophylaxis (aim 1) due to preservation of immune responses (aim 2a) that may arise from prolonged viral antigen exposure prior to systemic infection (aim 3a). Those who remain seronegative despite continued high-level exposure to HIV-1 (despite counseling), may develop HIV-specific cell-mediated or humoral immune responses, greater natural killer cell activity, or expression of protective host restriction factors (aim 2b), which could arise from viral exposure that is contained by the antiviral drug (aim 3b). We will also determine whether drug resistant infections occur more commonly during chemoprophylaxis exposure, and whether the drug resistant viruses predominate over time even after chemoprophylaxis is stopped, which has implications for secondary transmission of drug resistant variants. Prevention trials using antiviral agents versus placebo offer unique opportunities to study the viral and host interactions that underlie transmission, establishment of the plasma viral RNA setpoint, and host protection despite exposure. This research aims to elucidate the mechanisms of chemoprophylactic success or failure, which is essential for predicting longer term benefits (and risks) and for designing the next generation of chemoprophylactic trials.