Extracellular vesicles in semen and genital HIV infection and immunity during heroin addiction and methadone or buprenorphine substitution therapy

海洛因成瘾和美沙酮或丁丙诺啡替代治疗期间精液中的细胞外囊泡和生殖器艾滋病毒感染和免疫

• 批准号: 9086328
• 负责人: Florian Hladik
• 金额: $ 52.84万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086328
• 关键词: AIDS prevention; Address; Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Behavioral; Biological; Biology; Blood; Buprenorphine; CCR5 gene; CXCR4 gene; Cells; Clinical; Comparative Study; Consequences of HIV; Data; Data Reporting; Dendritic Cells; Environment; Genital system; Goals; Grant; HIV; HIV Infections; HIV vaccine; HIV-1; Health; Heroin; Heroin Abuse; Heroin Dependence; Heroin Users; Human; Immune Targeting; Immune response; Immune system; Immunity; Immunocompromised Host; Immunosuppression; Immunosuppressive Agents; In Vitro; Individual; Infection; Knowledge; Langerhans cell; Leukocytes; Link; Liposomes; Literature; Macaca mulatta; Measures; Mediating; Messenger RNA; Methadone; Modeling; Mucous Membrane; Naloxone; Nature; Nucleic Acids; Opiate Addiction; Opioid; Opioid Receptor; Outcome; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Predisposition; Prevention strategy; Property; Psyche structure; RNA; RNA Sequences; RNA Transport; Reporting; Research; Risk; SIV; Sampling; Seminal fluid; T cell response; T-Lymphocyte; TLR4 gene; Testing; Time; Vaccinated; Vaccination; Vaccine Antigen; Vagina; Virion; Virus; adaptive immunity; base; combinatorial; experience; extracellular; extracellular vesicles; fighting; functional outcomes; improved; in vivo; insight; intraepithelial; medication-assisted treatment; non-drug; opioid use; particle; receptor; research study; response; sexual HIV transmission; transmission process

 DESCRIPTION (provided by applicant): We have recently shown that human semen contains trillions of extracellular vesicles (SEV) carrying small extracellular RNA (exRNA) molecules that may regulate the immune system (Nucleic Acids Research, 42:7290-7304, 2014). In unpublished studies, we have found that SEV suppress adaptive T cell responses, most likely by affecting antigen presentation. SEV also associate with HIV virions in vitro and in our hands enhance HIV susceptibility, although another group recently reported the opposite. Ultimately, SEV likely impact HIV infection, both by directly interacting with HIV and its target cells, and by compromising protective T cell immunity against HIV. Opioids too affect the immune system, although the exact mechanisms and functional outcomes are not well- understood. Heroin abuse leads to an immunocompromised state and increases HIV susceptibility, but the behavioral and biological causes for this are difficult to untangle. Heroin addiction is often treated with long- term methadone or buprenorphine medication, two opioids whose immunological properties and effects on HIV infection also remain unclear. Thus, the interplay of extracellular vesicles in semen and opioid use may have important consequences for HIV infection and the immune system, and this proposal will investigate these connections. We will determine the effects of SEV on HIV infection in a vaginal explant model and dissect the nature and extent of SEV- mediated inhibition of adaptive T cell responses, including to HIV vaccination. We will perform comparative studies of HIV susceptibility, adaptive T cell responses and SEV biology (exRNA composition and function) in blood and semen samples from normal donors, as well as heroin users before and three months after starting assisted methadone or buprenorphine treatment. The three opioids will also be tested in culture, because expression of the Opioid Receptor-Like 1 receptor on vaginal leukocytes (our data), and reports of other non- opioid receptors such as Toll-like receptor 4, indicate that opioids could directly affect leukocyt biology. SEV and opioid interactions will be addressed in combinatorial experiments. These studies will deepen our understanding of how opioids and extracellular vesicles in semen, alone or in conjunction, impact sexual HIV transmission. Knowledge of these effects will help to improve HIV vaccination outcomes, focus other HIV prevention strategies, and provide new information on the clinical benefits of methadone versus buprenorphine substitution therapy.

 描述（由适用提供）：我们最近表明，人类精液中含有数万亿个携带小细胞外RNA（EXRNA）分子的细胞外蔬菜（SEV），这些分子可能调节免疫系统（核酸研究，42：7290-7304，2014）。在未发表的研究中，我们发现SEV抑制了适应性T细胞反应，最有可能通过影响抗原表现来抑制。 SEV在体外还与HIV病毒相关联，在我们手中增强了HIV的敏感性，尽管另一组最近报告了相反的情况。最终，SEV可能通过直接与HIV及其靶细胞相互作用以及通过 损害受HIV的受保护的T细胞免疫组织性。阿片类药物也影响了免疫系统，尽管确切的机制和功能结果并不理解。海洛因滥用导致免疫力低下的状态并增加了艾滋病毒的敏感性，但是为此，行为和生物学原因很难解开。海洛因成瘾通常是用长期的方法加多酮或丁丙诺啡药物治疗的，两种阿片类药物的免疫学特性以及对HIV感染的影响也尚不清楚。这，提取的蔬菜在精液和OID使用中的相互作用可能对HIV感染和免疫系统产生重要影响，该建议将研究这些联系。我们将确定SEV在阴道外植体模型中对HIV感染的影响，并剖析SEV介导的自适应T细胞反应的抑制性质和程度，包括对HIV疫苗接种。我们将对来自正常供体的血液和精液样本以及启动辅助辅助方法或丁丙诺啡治疗后三个月的血液和精液样本中的HIV敏感性，适应性T细胞反应和SEV生物学（EXRNA组成和功能）进行比较研究。这三种阿片类药物也将在培养中进行测试，因为在阴道白细胞（我们的数据）上表达类似阿片受体的1受体的表达，以及其他非阿片类受体（例如Toll类受体4）的报道，表明阿片类药物可以直接影响白细胞生物学。 SEV和阿片类药物相互作用将在组合实验中解决。这些研究将加深我们对阿片类药物和细胞外蔬菜的理解，单独或共同影响性HIV传播。了解这些影响将有助于改善HIV疫苗接种结果，集中其他预防HIV策略，并提供有关Meadadone与丁丙诺啡替代治疗的临床益处的新信息。