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

 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艾滋病毒污染的精液/精浆（SP）。SP含有多种促炎因子，这些促炎因子可通过促进细胞因子/趋化因子的产生来促进HIV传播，所述细胞因子/趋化因子募集容许细胞，增强HIV穿过生殖器上皮的易位，并激活HIV基因转录。这些因素的水平已被证明是在HIV感染过程中改变，与HIV感染的个体一般窝藏在SP的各种促炎细胞因子的水平较高。我们和其他人已经广泛研究了SP成分的属性，无论是关于他们的能力，以促进HIV感染和他们的能力，创造一个炎症状态有利于HIV复制。然而，SP中的一类因子很少受到关注，是外泌体，一种小的细胞外囊泡，其中数万亿通常存在于单个射精中。外来体是 重要的细胞间信号转导和诱导各种炎症或免疫调节反应。尽管许多研究已经表征了来自未感染和HIV感染个体的血浆来源的外泌体，但很少有人了解精液外泌体与HIV传播之间的关系。在这个R21中，我们测试了HIV感染改变SP外泌体组成的假设，以及来自HIV感染男性的SP外泌体可以诱导炎症并促进对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中外来体的数量、组成和RNA货物来实现这一点。然后在目标2中，我们将直接测试来自HIV感染男性的外来体是否有助于SP诱导生殖器粘膜内衬细胞中炎症的能力，以及这些外来体是否可以增加允许细胞对HIV感染的易感性。这些研究将是第一个表征来自HIV感染男性的SP外泌体的研究，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。

 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.