The effect of HIV infection on CD4 T cell immunity to Mycobacterium tuberculosis

项目摘要/摘要 感染结核分枝杆菌(Mtb)导致1000万活动性结核病(TB)病例 每年由一种感染性病原体引起，是导致死亡的首要原因。尽管保护性的相关因素 对结核分枝杆菌的免疫没有明确的定义，与人类免疫缺陷病毒(HIV)混合感染是一种重要的 活动性肺结核发病的危险因素。此外，结核病风险的增加在以下方面也是显而易见的 艾滋病毒血清转换的第一年，表明对结核分枝杆菌的免疫力受损发生在艾滋病毒感染后的早期。 尽管有令人信服的证据表明艾滋病毒感染与CD4T细胞功能障碍有关，但分子 HIV感染损害CD4T细胞对结核分枝杆菌的反应的机制尚不清楚。这项提案的重点是 目的是确定HIV感染和治疗对表型、功能、表观基因组和 CD4T细胞对结核分枝杆菌的转录组反应。我们将利用从一口独特的井中采集的血液样本- 描述了肯尼亚蒙巴萨艾滋病毒感染高危妇女的纵向队列，以测试 假设：(I)HIV感染改变了CD4T细胞的表观基因组和转录组以促进 功能障碍的CD4T细胞的分化；以及(Ii)在艾滋病毒之前早期开始抗逆转录病毒治疗 诱导的CD4T细胞缺陷，保留了CD4T细胞反应的分子程序和功能能力 这可能有助于加强对结核分枝杆菌的免疫控制。我们将使用纵向样本来进行高- 用三维流式细胞术确定总的和结核分枝杆菌特异性的CD4T细胞的表型和功能 在感染艾滋病毒之后，以及抗逆转录病毒治疗前后。在每个时间点，我们还将定义染色质 可及性景观、DNA甲基组和总CD4T细胞群体的转录组。最后，我们将 使用尖端的单细胞RNA测序来确定艾滋病毒感染和治疗对 结核分枝杆菌特异性CD4T细胞的转录状态。这些研究将产生前所未有的、新颖的见解 HIV感染中CD4T细胞的表型、功能、转录和表观遗传学特征。而且，我们的 全基因组研究将确定HIV感染中CD4T细胞的分子程序，并可能确定 新的基因、途径和基于转录因子的调控模块可以被利用来增强 耐久的CD4T细胞介导的结核分枝杆菌控制。

Project Summary / Abstract Infection with Mycobacterium tuberculosis (Mtb) results in 10 million cases of active tuberculosis (TB) disease each year and is the leading cause of death due to a single infectious agent. Although the correlates of protective immunity to Mtb are not clearly defined, co-infection with human immunodeficiency virus (HIV) is a significant risk factor for development of active TB disease. Moreover, the increased risk of TB disease is evident within the first year of HIV seroconversion, suggesting that impairment of immunity to Mtb occurs early after HIV infection. Although there is compelling evidence that HIV infection is associated with CD4 T cell dysfunction, the molecular mechanisms by which HIV infection impairs CD4 T cell responses to Mtb are unknown. The focus of this proposal is to determine the effect of HIV infection and treatment on the phenotype, function, epigenome and transcriptome of CD4 T cell responses to Mtb. We will leverage blood samples collected from a unique, well- characterized longitudinal cohort of women at high-risk for HIV infection in Mombasa, Kenya to test the hypotheses that (i) HIV infection modifies the epigenome and transcriptome of CD4 T cells to promote differentiation of dysfunctional CD4 T cells; and (ii) early initiation of antiretroviral therapy (ART), prior to HIV- induced CD4 T cell deficiency, preserves the molecular program and functional capacity of CD4 T cell responses that may contribute to enhanced immune control of Mtb. We will use longitudinal samples to conduct high- dimensional flow cytometry to define the phenotype and function of total and Mtb-specific CD4 T cells before and after HIV infection, and before and after ART. At each time point, we will also define the chromatin accessibility landscape, DNA methylome, and transcriptome of the total CD4 T cell population. Lastly, we will use cutting edge, single-cell RNA-sequencing to determine the effect of HIV infection and treatment on the transcriptional state of Mtb-specific CD4 T cells. These studies will generate unprecedented, novel insights into the phenotypic, functional, transcriptomic, and epigenetic profiles of CD4 T cells in HIV infection. Moreover, our genome-wide studies will define the molecular program of CD4 T cells in HIV infection and will potentially identify novel genes, pathways, and transcription factor-based regulatory modules that can be leveraged to enhance durable CD4 T cell-mediated control of Mtb.