Chemoprophylaxis and HIV-Host Interactions

化学预防和 HIV 宿主相互作用

• 批准号: 7596309
• 负责人: Robert M. Grant
• 金额: $ 90.21万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596309
• 关键词: AIDS prevention; Abstinence; Address; Adverse effects; Africa; Animal Model; Antigens; Antiviral Agents; Asia; Attenuated; Benefits and Risks; Biological; Biological Assay; Biological Preservation; Blinded; CD4 Positive T Lymphocytes; Case Study; Cell Count; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Chemoprophylaxis; Clinical Trials; Complement; Counseling; Disease Progression; Drug Exposure; Drug resistance; Effectiveness; Enrollment; Evaluation; Event; Exposure to; Failure; Foundations; Funding; Gene Expression; Grant; HIV; HIV Seropositivity; HIV-1; HIV-1 drug resistance; Hour; Human; Immune; Immune response; Individual; Infection; International; Knowledge; Laboratories; Latin America; Lead; Local Microbicides; Lymphocyte; Measures; Mediating; Meta-Analysis; Natural Killer Cells; Nucleic Acids; Oral; Outcome Assessment; Participant; Persons; Placebos; Plasma; Prevention; Principal Investigator; RNA; Randomized; Research; Research Support; Reverse Transcriptase Inhibitors; Risk; Role; SIV; Safety; Serological; Specimen; Systemic infection; T-Lymphocyte; Tenofovir disoproxil fumarate; Testing; Time; Treatment Protocols; United States; United States National Institutes of Health; Ursidae Family; Variant; Viral; Viral Antigens; Viremia; Woman; Work; attenuation; condoms; cost effectiveness; design; drug resistant virus; emtricitabine; high risk; insight; men; next generation; nonhuman primate; novel strategies; prevent; programs; prophylactic; prospective; protective effect; response; success; transmission process; vaccine candidate; viral RNA; viral detection; virus host interaction

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.

描述（由申请人提供）：联合国艾滋病规划署估计，尽管人们普遍了解禁欲、减少性伴侣和使用安全套的保护作用，但每天仍有 14,000 例新的 HIV-1 感染发生。目前尚无已知的候选疫苗或外用杀菌剂具有保护作用，并且强化咨询不足以完全阻止传播。预防艾滋病毒的新方法值得紧急评估。这是一个竞争性的延续申请，旨在了解每日口服抗病毒药物对血清阴性人群预防 HIV-1 的病毒学和免疫学影响。自 24 个月前启动以来，该项目通过支持血清转化器耐药性的深入评估以及病毒学、免疫学和药理学分析所需样本的储存，在国际化学预防研究中发挥了重要作用。与以前一样，该项目的科学目标是检验这样的假设：与安慰剂相比，化学预防可能具有持久的益处（或风险），其持续时间超出了化学预防治疗的期限，包括由于在全身性感染之前长期暴露于病毒抗原而可能引起的免疫反应（目标 2a）的保留，因此尽管进行了化学预防（目标 1），但仍被感染的人的感染过程得到了减弱。 感染（目标 3a）。那些尽管持续高水平暴露于 HIV-1（尽管进行咨询）但仍保持血清阴性的人，可能会产生 HIV 特异性细胞介导或体液免疫反应、更强的自然杀伤细胞活性或表达保护性宿主限制因子（目标 2b），这可能是由于抗病毒药物所包含的病毒暴露所致（目标 3b）。我们还将确定在化学预防暴露期间耐药感染是否更常见，以及即使在化学预防停止后，随着时间的推移，耐药病毒是否仍占主导地位，这对耐药变异体的二次传播具有影响。使用抗病毒药物与安慰剂进行的预防试验提供了独特的机会来研究传播背后的病毒和宿主相互作用、血浆病毒RNA设定值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，这对于预测长期获益（和风险）和设计下一代化学预防试验至关重要。