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。目前还没有已知的候选疫苗或局部杀微生物剂可以保护人类免受HIV-1感染。因此，需要紧急评估预防艾滋病毒的新方法。认识到这一情况，美国国立卫生研究院和比尔及梅林达·盖茨基金会正在柬埔寨赞助一项随机临床试验，研究每日口服替诺福韦与安慰剂的安全性和有效性。替诺福韦是一种有效的HIV-1复制抑制剂，已被批准用于治疗艾滋病，并在动物模型中具有预防作用。正在进行的临床试验将评估替诺福韦化学预防是否能降低治疗期间的血清转换率。同一组研究人员现在提议扩展这项工作，以验证与安慰剂相比，每日口服替诺福韦可能具有持久的益处（或风险）的假设，这些益处超出了化学预防治疗的时间，包括由于免疫反应（目标2a）在长时间的病毒抗原暴露（目标3a）下保持免疫反应（目标2a），在那些尽管进行化学预防治疗（目标1）的感染者中感染过程的衰减。这些益处的持久性将在纵向随访期间进行评估。那些在化学预防期间尽管暴露于病毒，但仍呈血清阴性的人可能由于暴露于抗病毒药物（目标3b）所含的病毒而产生艾滋病毒特异性免疫反应（目标2b）。由于测量到的免疫反应或其他因素，先前暴露于化学预防的血清阴性个体可能对HIV-1感染产生部分抗性，如果发生血清转换，这些因素将降低血清发病率或减轻感染过程（目标4）。我们还将确定耐药感染是否在化学预防暴露期间和之后更常发生，以及耐药病毒是否在化学预防停止后仍占主导地位，这对继发传播有影响。完成替诺福韦与安慰剂随机对照试验的血清转化和血清阴性妇女的前瞻性队列研究具有独特的价值。化疗后预防的益处和风险的评估直接关系到这种预防HIV-1的新方法的实用性。即使发现替诺福韦化学预防在预防血清转化方面无效，所提出的队列将提供独特的有价值的见解，了解抗病毒药物对病毒复制的极早期抑制如何影响控制HIV-1疾病进展的病毒-宿主相互作用。

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 and condom use. There are no vaccine candidates or topical microbicides that are known to protect humans from HIV-1 infection. Hence, novel approaches to HIV prevention warrant urgent evaluation. Recognizing this situation, the National Institutes of Health and the Bill and Melinda Gates Foundation are sponsoring a randomized clinical trial of the safety and effectiveness of daily oral tenofovir versus placebo in Cambodia. Tenofovir is a potent inhibitor of HIV-1 replication that is licensed for treatment of AIDS and has prophylactic effects in animal models. The clinical trial in progress will evaluate whether chemoprophylaxis with tenofovir reduces that rate of seroconversion during the period of treatment. The same group of investigators now proposes to extend this work to test the hypothesis that daily oral tenofovir 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) from prolonged viral antigen exposure (aim 3a). The durability of these benefits will be assessed during longitudinal follow-up. Those who remain seronegative despite viral exposure during chemoprophylaxis may develop HIV-specific immune responses (aim 2b) due to viral exposure that is contained by the antiviral drug (aim 3b). Seronegative individuals previously exposed to chemoprophylaxis may become partially resistant to HIV-1 infection due to the measured immune responses, or other factors, that will decrease seroincidence or attenuate the course of infection if seroconversion occurs (aim 4). We will also determine whether drug resistant infections occur more commonly during and after chemoprophylaxis exposure, and whether the drug resistant viruses remain predominate over time even after chemoprophylaxis is stopped, which has implications for secondary transmission. The proposed prospective cohort of seroconverting and seronegative women who have completed the randomized trial of tenofovir versus placebo are uniquely valuable. The evaluation of post-chemoprophylactic benefits and risks bears directly on the utility of this novel approach to HIV-1 prevention. Even if tenofovir chemoprophylaxis is found to be ineffective in preventing seroconversion, the proposed cohort will provide uniquely valuable insights into how extremely early suppression of viral replication with antiviral agents may influence viral-host interactions that govern HIV-1 disease progression.