Chemoprophylaxis and HIV-Host Interactions

化学预防和 HIV 宿主相互作用

• 批准号: 7393773
• 负责人: Robert M. Grant
• 金额: $ 74.93万
• 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/7393773
• 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; Daily; 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; Score; Serological; Specimen; Systemic infection; T-Lymphocyte; Tenofovir disoproxil fumarate; Testing; Time; Treatment Protocols; United States; United States National Institutes of Health; Ursidae Family; Vaccines; Variant; Viral; Viral Antigens; Viremia; Woman; Work; attenuation; condoms; cost effectiveness; day; design; drug resistant virus; emtricitabine; insight; men; next generation; nonhuman primate; novel strategies; prevent; programs; prophylactic; prospective; protective effect; response; success; transmission process; 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，尽管人们广泛了解禁欲、减少性伴侣和使用避孕套的保护作用，但每天仍有14，000例新的HIV-1感染病例发生。没有候选疫苗或局部杀微生物剂已知是保护性的，强化咨询不足以完全阻止传播。新的艾滋病毒预防方法需要紧急评估。这是一个竞争性的继续申请项目，旨在了解每日口服抗病毒药物用于血清阴性者预防HIV-1的病毒学和免疫学意义。自24个月前成立以来，该项目在国际化学预防研究组合中发挥了重要作用，支持对耐药性血清转化者进行深入评价，并储存病毒学、免疫学和药理学分析所需的标本。和以前一样，该项目的科学目标是检验化学预防可能具有持久益处的假设（或风险），与安慰剂相比，超过化学预防治疗期，包括由于免疫反应的保留而使尽管进行了化学预防（目标1）但仍受感染者的感染过程减弱（目标2a）这可能是由于在全身感染之前长期接触病毒抗原引起的（目标3a）。那些尽管持续高水平暴露于HIV-1（尽管咨询）但仍保持血清阴性的患者，可能会出现HIV特异性细胞介导或体液免疫应答，更强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，以及耐药病毒是否在化学预防停止后随时间推移而占主导地位，这对耐药变异的继发性传播有影响。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的相互作用，这些相互作用是传播的基础，建立血浆病毒RNA设定点，以及尽管暴露也能保护宿主。本研究旨在阐明化学预防成功或失败的机制，这对于预测长期益处（和风险）和设计下一代化学预防试验至关重要。