Dissecting the mechanisms of HIV-1 infection and inflammatory signaling in human lymphoid tissue

项目摘要/摘要 HIV-1感染导致一种不治之症，导致慢性炎症，导致共病。 最近的证据表明，嘌呤能受体和下游炎症体具有重要作用。 HIV-1进入和推动炎症的信号媒介和重要贡献者。初步数据 表明嘌呤能信号通路的抑制剂可以减少HIV-1感染和炎性细胞因子信号通路。 我们的目标是阐明HIV-1在淋巴组织中介导炎症信号的作用。这项研究是 一位将汇集艾滋病毒病毒学专业知识的早期研究人员、内科科学家的提议， 免疫学和基因组学测试以下目标：1)区分炎性细胞和间质细胞类型 外周血液、游离扁桃体和扁桃体阻塞中的HIV相关炎症信号所需的。2) 通过相关成像和转录分析研究感染细胞和旁观者细胞的分化模式 受感染的扁桃体块。所提出的方法是新颖的，因为它们利用了最近开发的体外实验 人类扁桃体感染模型和单细胞成像和基因表达平台，将允许 在单细胞水平上了解与HIV-1感染相关的炎症信号。这个 研究人员和合作者提供免费的专业知识和西奈山健康中心的设施 系统唯一能够支持这些研究的核心设施，大型患者队列，以及 制度保障。位于西奈山的伊坎医学院表现出了对职业生涯的承诺 这一早期首席调查员的发展。我们的目标是发展一个成功的职业生涯 一位独立的内科科学家，研究HIV-1感染及其下游的发病机制 HIV-1感染中的信号转导，目标是寻找治疗HIV-1感染的关键治疗药物 以及在了解和逆转HIV-1潜伏在治疗方法的发展方面。

PROJECT SUMMARY/ABSTRACT HIV-1 infection causing an incurable disease resulting in chronic inflammation that leads to comorbidities. Recent evidence has suggested an important role of purinergic receptors and downstream inflammasome signaling mediators and important contributors to HIV-1 entry and in driving inflammation. Preliminary data indicate that inhibitors of purinergic signaling reduce both HIV-1 infection and inflammatory cytokine signaling. Our goal is to elucidate the role of HIV-1 in mediating inflammatory signaling in lymphoid tissue. This study is the proposal of an early stage investigator physician scientist who will bring together expertise in HIV virology, immunology, and genomics to test the following aims: 1) Differentiating the inflammatory and stromal cell types required for HIV-associated inflammatory signaling in peripheral blood, dissociated tonsils and tonsil blocks. 2) Differentiating patterns of infected and bystander cells through correlative imaging and transcriptomic analysis of infected tonsil blocks. The methods proposed are novel in that they utilize a recently developed ex vivo human tonsil infection model and a single cell imaging and gene expression platform that will allow for understanding the inflammatory signaling that is associated with HIV-1 infection on a single cell level. The investigators and collaborators offer complimentary expertise and the facilities at the Mount Sinai Health System are uniquely capable of supporting these studies with core facilities, large patient cohorts, and institutional support. The Icahn School of Medicine at Mount Sinai has demonstrated commitment to the career development of this early stage principal investigator. The goal is to develop a successful career of the PI as an independent physician scientist in dissecting out the pathogenesis of the HIV-1 infection and downstream signaling in HIV-1 infection with the goal of finding key therapeutic agents in the treatment of HIV-1 infection and inflammation and in understanding and reversing HIV-1 latency in the development of a cure.