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 In unpublished studies, we have found that SEV suppress adaptive T cell responses, most likely by affecting antigen presentation.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（由申请人提供）：我们最近表明，人类精液含有数万亿个细胞外囊泡（SEV），其携带可以调节免疫系统的小细胞外RNA（exRNA）分子（Nucleic Acids Research，42：7290-7304，2014）。在未发表的研究中，我们发现 SEV 很可能通过影响抗原呈递来抑制适应性 T 细胞反应。 SEV 还在体外和我们手中与 HIV 病毒颗粒相关，从而增强了 HIV 易感性，尽管另一个研究小组最近报告了相反的情况。最终，SEV 可能通过与 HIV 及其靶细胞直接相互作用以及通过 损害针对 HIV 的保护性 T 细胞免疫力。阿片类药物也会影响免疫系统，尽管确切的机制和功能结果尚不清楚。海洛因滥用会导致免疫功能低下并增加艾滋病毒易感性，但其行为和生物学原因很难弄清楚。海洛因成瘾通常通过长期使用美沙酮或丁丙诺啡药物来治疗，这两种阿片类药物的免疫特性和对艾滋病毒感染的影响尚不清楚。因此，精液中细胞外囊泡和阿片类药物使用的相互作用可能对艾滋病毒感染和免疫系统产生重要影响，本提案将研究这些联系。我们将在阴道外植体模型中确定 SEV 对 HIV 感染的影响，并剖析 SEV 介导的适应性 T 细胞反应（包括 HIV 疫苗接种）抑制的性质和程度。我们将对正常捐献者以及海洛因使用者在开始辅助美沙酮或丁丙诺啡治疗前和三个月后的血液和精液样本中的 HIV 易感性、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物中进行测试，因为阴道白细胞上阿片类受体样 1 受体的表达（我们的数据）以及其他非阿片类受体（如 Toll 样受体 4）的报告表明阿片类药物可能直接影响白细胞生物学。 SEV 和阿片类药物的相互作用将在组合实验中得到解决。这些研究将加深我们对精液中阿片类药物和细胞外囊泡如何单独或联合影响艾滋病毒性传播的理解。了解这些影响将有助于改善艾滋病毒疫苗接种结果，关注其他艾滋病毒预防策略，并提供有关美沙酮与丁丙诺啡替代疗法的临床益处的新信息。