PrEP and protective immune responses against HIV-1

PrEP 和针对 HIV-1 的保护性免疫反应

基本信息

批准号：
8448122
负责人：
Jared Baeten
金额：
$ 63.67万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448122
关键词：
African Animals Anti-Retroviral Agents Antigens Antiviral Agents Biopsy Specimen Blood CD4 Lymphocyte Count Clinical Trials Controlled Clinical Trials Couples Dendritic Cells Development Disease Dose Double-Blind Method Exposure to Frequencies Future Genital system HIV-1 Heterosexuals Immune response Immunity Immunologics Immunology procedure Individual Infant Infection Intervention Measures Modeling Mucous Membrane Natural Killer Cells Nested Case-Control Study Oral Participant Peripheral Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Phase Phenotype Placebo Control Placebos Plasma Population Population Study Prevention strategy Prophylactic treatment Randomized Resistance Risk Sampling Sexual Partners Signal Transduction Site Source Surface T cell response Tenofovir Testing Time Tissue Sample Unsafe Sex Vaccines Viral Viral Physiology Woman arm efficacy trial emtricitabine follow-up immunogenicity improved innovation multidisciplinary nonhuman primate peripheral blood preclinical study prevent prophylactic prospective protective effect response sex simian human immunodeficiency virus

项目摘要

DESCRIPTION (provided by applicant): Pre-exposure prophylaxis (PrEP), in which HIV-1 uninfected persons use oral or topical antiretrovirals to protect against sexual HIV-1 acquisition, is one of the most promising new HIV-1 prevention strategies. It has been hypothesized that PrEP, by aborting infections through direct anti-viral activity, may allow HIV-1 specific immune responses to develop in exposed persons. In non-human primate models, T cell responses in blood recognizing SHIV antigens were achieved half of animals receiving PrEP. A "chemotherapeutic" effect of PrEP could enhance PrEP's efficacy for preventing HIV-1 acquisition, blunt early HIV-1 replication for PrEP breakthrough infections, improve immunogenicity and efficacy of a partially-effective HIV-1 vaccine, and provide anti-HIV-1 protection after PrEP is discontinued. PrEP clinical trials provide a unique opportunity to characterize anti-HIV-1 immune responses in persons on PrEP (compared directly to those on placebo), explore mechanisms for PrEP protection, and anticipate PrEP as "chemovaccination" paired with candidate HIV-1 vaccines. We are conducting the largest phase III efficacy trial of PrEP - the Partners PrEP Study, a randomized, double-blind, placebo-controlled, clinical trial of oral tenofovir and emtricitabine/tenofovir PrEP among HIV-1 uninfected partners in 4758 African HIV-1 serodiscordant couples. In July 2011, we demonstrated in the Partners PrEP Study that daily oral PrEP using tenofovir and emtricitabine/tenofovir significantly reduced HIV-1 acquisition risk, by 62% (p=0.0003) and 73% (p<0.0001) respectively. We propose to explore anti-HIV-1 responses in HIV-1 exposed but uninfected persons receiving PrEP, evaluate the relationship between anti-HIV-1 immune responses and protection against HIV-1 acquisition and control of viral replication in breakthrough infections observed during prospective follow-up, and, in an exploratory study, collect and test mucosal samples from persons on PrEP to evaluate immune responses at the site of HIV-1 exposure. Our proposed project is innovative in its use of a randomized, placebo-controlled clinical trial population, allowing unbiased, longitudinal comparisons of the effect of PrEP (versus placebo) on induction of HIV-1-specific immune responses, in the study population of HIV-1 serodiscordant couples, allowing precise definition of the degree of HIV-1 exposure, and in its application of state-of-the-art immunologic assays to study the impact of PrEP on HIV-1 protection and control of viral replication. We will 1) determine the frequency, magnitude, and persistence of anti-HIV-1 innate and adaptive immune responses in persons receiving PrEP compared to placebo, 2) assess the effect of anti- HIV-1 responses on protection against HIV-1 acquisition (controlling for PrEP randomization arm) and control of HIV-1 replication (in those with breakthrough infections in spite of PrEP), and 3) measure anti-HIV- 1 innate and adaptive immune responses in mucosal biopsy samples from HIV-1 uninfected persons on PrEP compared to placebo. Our testing will focus on peripheral blood T cell responses, as these have been found most frequently as a potential correlate of HIV-1 resistance in highly-exposed HIV-1 seronegative persons, and we will also test for peripheral innate immune responses (NK cell phenotyping and functional studies, dendritic cell phenotyping). In mucosal samples, we will test for both adaptive and innate immune responses. Our hypothesis is that PrEP allows for development of host immunity that will provide protection against HIV-1 infection and disease. We have assembled a multinational team with the multidisciplinary HIV-1 expertise necessary to execute the proposed studies. Our findings will be directly relevant to the development of a prophylactic HIV-1 vaccine or a combined PrEP-vaccine strategy that might offer greater protection against HIV-1 than either intervention alone.

描述（由申请人提供）：暴露前预防 (PrEP)，其中 HIV-1 未感染者使用口服或局部抗逆转录病毒药物来防止性行为感染 HIV-1，是最有前途的新型 HIV-1 预防策略之一。据推测，PrEP 通过直接抗病毒活性中止感染，可能使暴露于 HIV-1 的人产生特异性免疫反应。在非人类灵长类动物模型中，接受 PrEP 的动物中有一半实现了血液中识别 SHIV 抗原的 T 细胞反应。 PrEP 的“化疗”作用可以增强 PrEP 预防 HIV-1 获得的功效，削弱 PrEP 突破性感染的早期 HIV-1 复制，提高部分有效的 HIV-1 疫苗的免疫原性和功效，并提供抗 HIV-1 PrEP 停止后的保护。 PrEP 临床试验提供了一个独特的机会来表征 PrEP 患者的抗 HIV-1 免疫反应（直接与安慰剂组相比），探索 PrEP 保护机制，并预期 PrEP 作为与候选 HIV-1 疫苗配对的“化学疫苗”。我们正在进行最大的 PrEP III 期疗效试验 - 合作伙伴 PrEP 研究，这是一项随机、双盲、安慰剂对照临床试验，在 4758 名非洲 HIV-1 未感染 HIV-1 的伴侣中进行口服替诺福韦和恩曲他滨/替诺福韦 PrEP 临床试验血清不一致的夫妇。 2011 年 7 月，我们在 Partners PrEP 研究中证明，每日口服 PrEP 使用替诺福韦和恩曲他滨/替诺福韦可显着降低 HIV-1 感染风险，分别降低 62% (p=0.0003) 和 73% (p<0.0001)。我们建议探索接受 PrEP 的 HIV-1 暴露但未感染者的抗 HIV-1 反应，评估抗 HIV-1 免疫反应与预防 HIV-1 获得的保护以及前瞻性感染期间观察到的突破性感染中病毒复制的控制之间的关系随访，并在一项探索性研究中，收集并测试 PrEP 人群的粘膜样本，以评估 HIV-1 暴露部位的免疫反应。我们提出的项目的创新之处在于它使用了随机、安慰剂对照的临床试验人群，允许在 HIV 研究人群中对 PrEP（与安慰剂）对诱导 HIV-1 特异性免疫反应的效果进行无偏见的纵向比较-1 血清不一致对，允许精确定义 HIV-1 暴露程度，并应用最先进的免疫测定来研究 PrEP 对 HIV-1 保护和病毒复制控制的影响。我们将 1) 确定与安慰剂相比，接受 PrEP 的人抗 HIV-1 先天性和适应性免疫反应的频率、强度和持续性，2) 评估抗 HIV-1 反应对防止 HIV-1 感染的影响（控制 PrEP 随机分组）和控制 HIV-1 复制（尽管进行了 PrEP，但仍发生突破性感染），以及 3) 测量未感染 HIV-1 的粘膜活检样本中的抗 HIV-1 先天性和适应性免疫反应接受 PrEP 的人与安慰剂组的比较。我们的测试将重点关注外周血 T 细胞反应，因为在高度暴露于 HIV-1 血清阴性人群中，这些反应最常被发现与 HIV-1 耐药性存在潜在相关性，并且我们还将测试外周先天免疫反应（NK 细胞）表型和功能研究、树突状细胞表型）。在粘膜样本中，我们将测试适应性和先天免疫反应。我们的假设是 PrEP 可以促进宿主免疫力的发展，从而提供针对 HIV-1 感染和疾病的保护。我们组建了一支跨国团队，拥有执行拟议研究所需的多学科 HIV-1 专业知识。我们的研究结果将与预防性 HIV-1 疫苗或 PrEP 疫苗联合策略的开发直接相关，这些策略可能比单独的任何一种干预措施提供更好的针对 HIV-1 的保护。