Gut mucosal immunity to HIV-1 in controlled and progressive infection

描述（由申请人提供）：对HIV的免疫反应在很大程度上是在最容易接近的细胞室——外周血中进行的，它只包含所有淋巴细胞的2-3%。相反，体内至少一半的T细胞驻留在肠道相关淋巴组织（GALT）中。在感染早期，肠粘膜中的CD4+ T细胞迅速而深刻地耗竭，而这些细胞在外周循环中有显著的保存。开始抗逆转录病毒治疗通常会导致病毒载量的抑制和外周CD4+ T细胞计数的恢复，但肠道中CD4+ T细胞的重新聚集相当延迟和不完整。这些发现表明，肠道代表着一个独特的隔离病毒生态位。然而，肠道中HIV特异性T细胞的功能特征仍然不完整，特别是在“HIV控制者”中——在没有抗逆转录病毒治疗的情况下自发控制感染的个体。在这个应用中，我建议使用新颖的、最先进的功能分析来研究来自慢性进行性和受控HIV感染个体的肠道CD8+ T细胞的功能反应，这将允许对单个细胞进行多参数表征。我假设HIV特异性CD8+ T细胞的功能在慢性进行性感染中受损，但在控制感染中保留，HIV感染中的免疫功能障碍部分是HIV介导的正常肠道屏障破坏以及肠道树突状细胞改变的结果。具体来说，我提出肠内皮细胞上的粘附连接蛋白E-cadherin通过与HIV特异性CD8+ T细胞上的抑制受体KLRG1结合来介导CTL损伤。此外，我假设肠道dc损害了HIV介导的toll样受体（TLR）信号，从而导致慢性进行性感染个体的T细胞归巢功能失调。在这个申请中，我打算：1。利用细胞因子分泌和T细胞杀伤的新方法，确定进展性和控制性感染患者中HIV特异性肠道黏膜CD8+ T细胞的频率和功能能力。2 .通过评估E-cadherin结合抑制受体KLRG1对HIV特异性CD8+ T细胞的影响，确定肠道微环境对T细胞损伤的贡献；研究HIV编码的TLR配体在肠道DC生成维甲酸中的作用以及维甲酸对T细胞肠道归巢受体表达的影响。

DESCRIPTION (provided by applicant): The immune response to HIV has largely been studied in the most accessible compartment - the peripheral blood, which contains only 2-3% of all lymphocytes. In contrast, at least half of the body's T cells reside in gut associated lymphoid tissue (GALT). Early in infection there is a rapid and profound depletion of CD4+ T cells in the intestinal mucosa with notable preservation of these cells in the peripheral circulation. Initiation of antiretroviral therapy typically results in the suppression of viral load and restoration of CD4+ T cells counts in the periphery, but the repopulation of CD4+ T cells in the gut is considerably delayed and incomplete. These findings suggest that the gut represents a unique sequestered viral niche. The functional characterization of HIV specific T cells in the gut, however, remains incomplete, particularly in "HIV controllers" - individuals who spontaneously control infection in the absence of antiretroviral therapy. In this application I propose to study the functional responses of intestinal CD8+ T cells from individuals with chronic progressive and controlled HIV infection using novel, state-of-the-art functional assays that will allow the multiparametric characterization of single cells. I hypothesize that the function of HIV specific CD8+ T cells is impaired in chronic progressive infection but preserved in controlled infection and that immune dysfunction in HIV infection is in part a consequence of HIV mediated disruption of the normal intestinal barrier, as well as alterations in intestinal dendritic cells. Specifically, I propose that E-cadherin, an adherens junction protein present on gut endothelial cells, mediates CTL impairment by binding to the inhibitory receptor KLRG1 on HIV specific CD8+ T cells. Additionally, I hypothesize that intestinal DCs have impaired HIV mediated Toll-like receptor (TLR) signaling, which consequently results in dysfunctional T cell homing to the small intestine in individuals with chronic progressive infection. In this application I intend to: 1. Determine the frequency and functional capacity of HIV specific gut mucosal CD8+ T cells in patients with progressive and controlled infection using novel assays of cytokine secretion and T cell killing, 2. Define the contribution of the gut microenvironment to T cell impairment by assessing the effects of E-cadherin binding to the inhibitory receptor KLRG1 on HIV specific CD8+ T cells, and 3. Investigate the role of HIV encoded TLR ligands in intestinal DC production of retinoic acid and the effect of retinoic acid on T cell gut homing receptor expression. RELEVANCE (See instructions): The majority of the body's immune cells reside in the gastrointestinal tract and this region is intensely active during HIV infection. The effects of HIV in the gut, however, remain incompletely studied. We are developing new, state-of-the-art techniques to better assess the immune system in the gut of patients with progressive HIV disease and in unique individuals who are able to control infection without medicines. These studies will provide insights that will assist in the development of more effective therapies and vaccines against HIV.