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

摘要 全球每年有200万新的艾滋病毒感染病例。感染艾滋病毒仅仅是部分原因 可通过暴露、行为和伴发性传播感染来解释。的确有 越来越多的证据表明，局部和全身免疫激活可能会使靶细胞 易感染艾滋病毒的。已注意到免疫激活和艾滋病毒之间关系的研究 采集尚未配备来识别伴随这些AT-AT的特定疾病状态- 风险概况。因为潜伏的艾滋病毒蓄水池是在感染后几天内建立的，而且 HIV靶细胞的易感性通过免疫激活而改变，炎症状态在 获得艾滋病毒的时间可能会调节处于危险状态的细胞的数量，从而调节病毒的大小 潜伏的艾滋病病毒携带者。我们将确定调节艾滋病毒感染风险的炎症性特征 以及高危男男性接触者(MSM)中潜在病毒储备库的大小 在秘鲁利马建立了队列。我们将尝试确定以下原因的组成部分 免疫激活，包括持续和短暂的病毒感染、酒精和药物使用， 以及导致这种高风险免疫激活的性暴露。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访问、问卷调查和储存血液 样本。感染了HIV的男男性接触者参加了一项跟踪研究，并接受了抗逆转录病毒治疗 立即或在24周后接受治疗(ART)，并将在接下来的4周内继续随访 好几年了。在目标1中，我们将使用嵌套病例对照设计来比较细胞因子谱和 MSM中匹配时间点的新型病毒血清学检测(VirScan) 获取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感染前的激活和病毒感染可作为大小的预测指标 在感染艾滋病毒的男男性接触者中潜伏的病毒库。我们将建立统计模型来 描述艾滋病毒免疫激活的病毒和其他成分原因的作用 采集和储集层大小。我们研究的创新之处包括增加了 尖端技术评估对已知病毒感染的免疫反应(VirScan)，以 多维队列数据以更好地识别人类和细胞对艾滋病毒感染的易感性， 以及将炎症原因和免疫激活标志物在 在感染艾滋病毒前的接触时间非常短。我们预计，这项研究的结果将 提高我们对艾滋病毒易感性的病理生理学的理解，并允许进一步的工作 转向生物医学干预措施，以预防艾滋病毒感染和调节潜在的艾滋病毒宿主。

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.