The effect of HIV and cocaine abuse on semen exosome composition and function

HIV和可卡因滥用对精液外泌体组成和功能的影响

• 批准号: 9747024
• 负责人: Chioma M Okeoma
• 金额: $ 56.01万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9747024
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Address; Affect; Antiviral Agents; Binding Proteins; Biological Assay; Cell-Free System; Cells; Cocaine; Cocaine Abuse; Coitus; Complex; DNA; Data; Development; Disease Progression; Electrons; Epithelial Cells; Foundations; Goals; HIV; HIV Infections; HIV-1; Heterosexuals; Human; Illicit Drugs; Impairment; In Vitro; Individual; Infection; Inflammatory; Intrinsic factor; Investigation; Life Cycle Stages; Link; Lymphatic; Messenger RNA; Methods; Modeling; Molecular; Morphology; Murine Acquired Immunodeficiency Syndrome; Pathogenesis; Persons; Population; Process; RNA; RNA-Directed DNA Polymerase; Recording of previous events; Research Design; Research Personnel; Reverse Transcription; Risk; Role; Route; Seminal fluid; Sexual Transmission; Small RNA; Test Result; Therapeutic; Vagina; Variant; Virus; Virus Diseases; Woman; cocaine exposure; cocaine use; cytokine; density; design; efficacy evaluation; electron density; exosome; fitness; frontier; genetic information; mortality; novel; pandemic disease; particle; pathogen; prevent; protective factors; transmission process; vector

Abstract The AIDS pandemic remains a significant global problem with over 33.3 million persons currently infected with HIV and HIV-related illnesses claiming the lives of over 1.8 million individuals annually. Various studies have suggested a link between abuse of illicit drugs, including cocaine and increased risk of HIV transmission, accelerated HIV disease progression, and AIDS-related mortality. Women represent the fastest growing population of new HIV cases. It is estimated that more than 80% of HIV cases result from sexual transmission and semen is the primary vector. However, only about 0.1% of acts of heterosexual coitus with an infected individual result in HIV infection, suggesting that factors contained in semen may modulate the infectivity or fitness of HIV particles in semen. The underlying mechanisms of HIV transmission are not well understood. In spite of the progress in studies of HIV pathogenesis and the ability of various agents to suppress virus infection, methods to prevent HIV transmission still require more investigation. Recently, we showed that semen of healthy donors contain heterologous populations of exosomes that are morphologically distinct with respect to size and electron density. These exosomes contain different species of RNA (mRNA and small RNA), and inhibit infection with HIV. Our preliminary data reveal that similar to exosomes from the semen of healthy donors, exosomes purified from HIV infected donors potently block HIV infection while exosomes from HIV infected donors who use cocaine do not inhibit HIV. Our preliminary study further showed that HIV infection and cocaine use modulates RNA composition of semen exosomes. Importantly, lysed semen exosomes from both HIV negative and HIV infected donors but not donors who used cocaine inhibit reverse transcription of lysed HIV in a cell-free system, block the synthesis of HIV U5 DNA, and reverse transcription of U5 to Gag. These data indicate direct effect of semen exosomes on HIV reverse transcription. In this application, studies are designed to 1) determine the effect of HIV infection and cocaine abuse on the anti-HIV activity of semen exosomes, 2) determine the mechanisms of anti-HIV effect of semen exosomes, and 3) characterize the effects of donor HIV status and cocaine use on semen exosome composition. As sexual transmission is the main route for the spread of HIV and semen is the primary vector, the studies proposed in this application will address a new challenge for evaluation of the efficacy of semen exosomes as a protective factor against HIV and how donor HIV status and cocaine use modulate this function.

抽象的 艾滋病大流行仍然是一个重大的全球问题，目前超过3330万人 感染艾滋病毒和与艾滋病毒相关的疾病，每年超过180万人的生命。 各种研究表明，包括可卡因在内的非法药物滥用和增加之间有联系 艾滋病毒传播的风险，加速艾滋病毒疾病进展和与艾滋病相关的死亡率。女性 代表新的艾滋病毒案例增长最快的人群。据估计，超过80％的艾滋病毒 性传播和精液导致的病例是主要载体。但是，只有约0.1％ 具有感染个体感染的异性恋性行为的行为，表明因素 精液中包含的可能调节精液中HIV颗粒的感染性或适应性。基础 艾滋病毒传播的机制尚不清楚。尽管艾滋病毒研究取得了进展 发病机理和各种药物抑制病毒感染的能力，预防HIV的方法 传输仍然需要更多的调查。最近，我们展示了健康捐助者的精液 包含异泌体的异源种群，这些外泌体在形态上与大小相关 和电子密度。这些外泌体包含不同的RNA（mRNA和小RNA），以及 抑制艾滋病毒感染。我们的初步数据表明，类似于来自的外泌体 健康的供体，从受HIV感染的供体纯化的外泌体有效阻止HIV感染，而 使用可卡因的艾滋病毒感染者的外泌体不抑制艾滋病毒。我们的初步研究 表明HIV感染和可卡因使用调节精液外泌体的RNA组成。 重要的是，来自HIV阴性和HIV感染供体的裂解精液外泌体，但没有供体 使用可卡因抑制了无细胞系统中裂解HIV的逆转录，阻止了合成 HIV U5 DNA，并将U5逆转录到插科打g。这些数据表明精液的直接影响 HIV逆转录的外泌体。在此应用中，研究设计为1）确定 HIV感染和可卡因滥用对精液外泌体抗HIV活性的影响，2）确定 精液外泌体的抗HIV效应的机制，以及3）表征供体HIV的作用 精液外泌体组成上的状态和可卡因。因为性传播是 艾滋病毒和精液的传播是主要向量，本应用中提出的研究将 应对评估精液外泌体有效性作为保护因素的新挑战 反对艾滋病毒以及供体HIV状态和可卡因的使用如何调节此功能。