Chemoprophylaxis and HIV-Host Interactions

描述(由申请者提供)：联合国艾滋病规划署估计，尽管禁欲、减少伴侣和使用避孕套的保护作用广为人知，但每天仍有14,000例新的艾滋病毒-1感染病例。目前还没有候选疫苗或局部杀微生物剂具有保护性，而且密集的咨询还不足以完全阻止传播。迫切需要对预防艾滋病毒的新方法进行评估。这是一项旨在了解每日口服抗病毒药物对血清阴性患者预防艾滋病毒-1的病毒学和免疫学影响的项目的竞争性继续申请。自24个月前启动以来，该项目通过支持密集的血清转换者耐药性评估以及病毒学、免疫学和药理学分析所需的标本存储，在国际化学预防研究组合中发挥了重要作用。与以前一样，该项目的科学目标是检验这样一种假设，即与安慰剂相比，化学预防可能具有超越化学预防治疗期的持久益处(或风险)，包括由于保存了免疫反应(目标2a)，尽管化学预防但仍被感染者的感染病程缩短(目标2a)，这可能是由于在全身感染之前长期接触病毒抗原(目标3a)。那些尽管持续高水平暴露于艾滋病毒-1(尽管接受了咨询)但仍保持血清阴性的人，可能会出现艾滋病毒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(目标2b)，这可能是由于抗病毒药物(目标3b)所含的病毒暴露引起的。我们还将确定耐药感染是否在化学预防期间发生得更常见，以及耐药病毒是否在化学预防停止后随着时间的推移而占优势，这可能会导致耐药变异的二次传播。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，这些相互作用是传播的基础，建立了血浆病毒RNA设定点，并在暴露于病毒的情况下提供了宿主保护。这项研究旨在阐明化学预防成功或失败的机制，这对于预测较长期的益处(和风险)和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.