Characterization of Exosomes From Semen of Uninfected and HIV-Infected Men

未感染和 HIV 感染男性精液中外泌体的表征

• 批准号: 9228315
• 负责人: Nadia R Roan
• 金额: $ 19.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9228315
• 关键词: AIDS/HIV problem; Acute; Affect; Amyloid; Attention; Biological; CD4 Positive T Lymphocytes; Cells; Chronic; Data; Data Set; Disease; Endometrial; Enrollment; Epithelial; Epithelial Cells; Epithelium; Event; Exposure to; Female; Flow Cytometry; Genetic Transcription; Genital system; HIV; HIV Infections; HIV-1; Immune; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Lipids; Liquid substance; Mediating; Mucous Membrane; Plasma; Play; Predisposition; Production; Property; Prostaglandins; Proteins; RNA; Recruitment Activity; Role; Sampling; San Francisco; Seminal; Seminal Plasma; Seminal fluid; Sexually Transmitted Diseases; Signal Transduction; Source; TNF gene; Testing; Time; Transducers; Transforming Growth Factor beta; Vesicle; Viral Load result; Work; cellular targeting; chemokine; cohort; comparative; cytokine; exosome; extracellular vesicles; healthy pregnancy; immunoregulation; in vivo; macrophage; men; pathogen; permissiveness; public health relevance; release factor; reproductive tract; response; sexual HIV transmission; sperm cell; transcriptome sequencing; transcriptomics; transmission process

 DESCRIPTION (provided by applicant): The continuing spread of HIV/AIDS in people is predominantly fueled by sexual exposure to HIV-contaminated semen/seminal plasma (SP). SP harbors a variety of pro-inflammatory factors that may facilitate HIV transmission by promoting the production of cytokines/chemokines that recruit permissive cells, enhance the translocation of HIV across the genital epithelium, and activate HIV gene transcription. The levels of these factors have been shown to be altered during HIV infection, with HIV-infected individuals generally harboring higher levels of various pro-inflammatory cytokines in SP. We and others have extensively studied the properties of SP constituents, both with regards to their ability to promote HIV infection and their ability to create an inflammatory state favoring HIV replication. However, one class of factors in SP that has received little attention is exosomes, small extracellular vesicles of which trillions are typically present in a single ejaculate. Exosomes are important intercellular signal transducers and induce various inflammatory or immunomodulatory responses. Although numerous studies have characterized plasma-derived exosomes from both uninfected and HIV-infected individuals, very little has been done to understand the relationship between semen exosomes and HIV transmission. In this R21, we test the hypotheses that HIV infection alters the composition of exosomes in SP and that SP exosomes from HIV-infected men can induce inflammation and promote susceptibility to HIV infection. We will accomplish this by assessing in Aim 1 how HIV infection and ART treatment status affect the quantity, composition, and RNA cargo of exosomes in SP. Then in Aim 2, we will directly test the whether exosomes from HIV-infected men contribute towards the ability of SP to induce inflammation in cells lining the genital mucosa, and whether these exosomes can increase the susceptibility of permissive cells to HIV infection. These studies will be the first t characterize SP exosomes from HIV-infected men, and will lead to a better understanding of how these vesicles affect the early events of sexual transmission of HIV.

 描述（由申请人提供）：艾滋病毒/艾滋病在人群中的持续传播主要是由于性接触受艾滋病毒污染的精液/精浆（SP）所致。 SP 含有多种促炎因子，这些因子可能通过促进细胞因子/趋化因子的产生来促进 HIV 传播，这些细胞因子/趋化因子招募允许的细胞，增强 HIV 跨生殖器上皮的易位，并激活 HIV 基因转录。这些因子的水平已被证明在 HIV 感染期间发生改变，HIV 感染者通常在 SP 中含有较高水平的各种促炎细胞因子。我们和其他人广泛研究了 SP 成分的特性，包括它们促进 HIV 感染的能力以及它们产生有利于 HIV 复制的炎症状态的能力。然而，SP 中很少受到关注的一类因素是外泌体，即单次精液中通常存在数万亿个小的细胞外囊泡。外泌体是 重要的细胞间信号转导器并诱导各种炎症或免疫调节反应。尽管许多研究已经对来自未感染者和 HIV 感染者的血浆来源的外泌体进行了表征，但对于精液外泌体与 HIV 传播之间的关系却知之甚少。在这个 R21 中，我们测试了以下假设：HIV 感染改变了 SP 中外泌体的组成，并且 HIV 感染男性的 SP 外泌体可以诱发炎症并增加对 HIV 感染的易感性。我们将通过在目标 1 中评估 HIV 感染和 ART 治疗状态如何影响 SP 中外泌体的数量、组成和 RNA 货物来实现这一目标。然后在目标2中，我们将直接测试来自HIV感染者的外泌体是否有助于SP诱导生殖器粘膜细胞炎症的能力，以及这些外泌体是否可以增加允许细胞对HIV感染的易感性。这些研究将首次表征 HIV 感染男性的 SP 外泌体，并将有助于更好地了解这些囊泡如何影响 HIV 性传播的早期事件。