Determining the component causes of systemic immune activation that moderate HIV acquisition and establishment of the latent viral reservoir

摘要 全世界每年有200万新的艾滋病毒感染者。艾滋病毒感染只是部分原因 通过暴露、行为和并发性传播感染来解释。有 越来越多的证据表明，局部和全身免疫激活可能使靶细胞更多地 易感染艾滋病病毒。已经注意到与免疫激活和HIV相关的研究 采集尚未配备识别伴随这些的特定疾病状态的设备- 风险概况。因为潜伏的HIV病毒库在感染后的几天内就建立起来了， HIV靶细胞的易感性通过免疫激活而改变， 艾滋病毒获得的时间可能会调节处于危险中的细胞的数量，因此， 潜伏的HIV宿主我们将确定调节艾滋病毒感染风险的炎症特征 和潜伏病毒库的大小之间的高风险男性与男性发生性关系（MSM），在一个 在秘鲁利马建立了队列。我们将试图确定的组成原因， 免疫激活，包括持续和短暂的病毒感染，酒精和物质使用， 和性接触会导致这种高风险的免疫激活在这群秘鲁人中， 对HIV阴性的男男性接触者进行每月一次的随访，问卷调查， 样品男男性行为者感染艾滋病毒后被纳入随访研究，并接受抗逆转录病毒治疗 立即或在24周后接受ART治疗，并将在接下来的4周内继续随访 年在目标1中，我们将使用巢式病例对照设计来比较细胞因子谱， 一种新的病毒血清学检测（VirScan），来自匹配的时间点，在MSM中， 获得艾滋病毒，以评估艾滋病毒感染的预测因素。在目标2中，我们将评估免疫 HIV感染前即刻存在的活化和病毒感染作为大小的预测因子 感染艾滋病病毒的男男性接触者体内潜伏的病毒库。我们将建立统计模型， 描述病毒和其他免疫激活因子对HIV的作用 采集和储层大小。我们研究的创新包括增加了 尖端技术，以评估对已知病毒感染的免疫反应（VirScan）， 多维队列数据，以更好地确定人类和细胞对艾滋病毒感染的易感性， 以及将炎症的原因和免疫激活的标志物联系起来的能力。 感染艾滋病毒前的接触期很短。我们希望这项研究的结果将 提高我们对HIV易感性的病理生理学的理解，并允许进一步的工作 （c）采取生物医学干预措施，预防艾滋病毒感染和调节潜伏的艾滋病毒库。

ABSTRACT There are 2 million new HIV infections in the world each year. Acquisition of HIV is only partially explained by exposure, behavior, and concurrent sexually transmitted infections. There is growing evidence that both local and systemic immune activation may make target cells more susceptible to HIV. Studies that have noted associations with immune activation and HIV acquisition have not been equipped to identify specific disease states that accompany these at- risk profiles. Because the latent HIV reservoir is established within days of infection, and susceptibility of HIV target cells is modified by immune activation, the inflammatory state at the time of HIV acquisition may modulate the quantity of cells at risk, and therefore the size of the latent HIV reservoir. We will identify inflammatory profiles that modulate risk of HIV acquisition and size of the latent viral reservoir among high-risk men who have sex with men (MSM) in an established cohort in Lima, Peru. We will attempt to determine the component causes of immune activation, including persistent and transient viral infections, alcohol and substance use, and sexual exposure that contribute to this high-risk immune activation. In this Peruvian cohort, HIV-negative MSM were followed with monthly visits, questionnaires, and banked blood samples. MSM who acquired HIV were enrolled in a follow-up study and received antiretroviral therapy (ART) immediately or after 24 weeks, and will continue to be followed for the next four years. In Aim 1, we will use a nested case-control design to compare cytokine profiles and a novel viral serologic assay (VirScan) from matching time-points in MSM who did and did not acquire HIV to evaluate predictors of HIV acquisition. In Aim 2, we will evaluate immune activation and viral infections present immediately prior to HIV acquisition as predictors for size of the latent viral reservoir in MSM who acquired HIV. We will build statistical models to describe the role of viruses and other component causes of immune activation on HIV acquisition and reservoir size, respectively. Innovations in our study include the addition of cutting edge technology to evaluate immune responses to known viral infections (VirScan) to multidimensional cohort data to better identify human and cellular susceptibility to HIV infection, and the ability to connect causes of inflammation and markers of immune activation within a very narrow exposure period prior to HIV acquisition. We expect that the results of this study will improve our understanding of the pathophysiology of HIV susceptibility and allow further work towards biomedical interventions to prevent HIV infection and modulate the latent HIV reservoir.