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

描述（由申请人提供）：对HIV的免疫应答主要在最容易接近的部分-外周血中进行研究，外周血仅含有所有淋巴细胞的2-3%。相比之下，至少有一半的身体T细胞存在于肠道相关淋巴组织（GALT）中。在感染的早期，肠粘膜中的CD 4 + T细胞迅速而深刻地消耗，这些细胞在外周循环中显著地保存。开始抗逆转录病毒治疗通常会抑制病毒载量并恢复外周血中的CD 4 + T细胞计数，但肠道中CD 4 + T细胞的再增殖会大大延迟且不完全。这些发现表明，肠道代表了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。在这个应用程序中，我建议使用新的，国家的最先进的功能检测，将允许单细胞的多参数表征研究慢性进行性和控制的HIV感染的个人的肠道CD 8 + T细胞的功能反应。我假设HIV特异性CD 8 + 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，并且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，我建议，E-钙粘蛋白，粘附连接蛋白存在于肠内皮细胞，介导CTL损伤的抑制性受体KLRG 1对HIV特异性CD 8 + T细胞的结合。此外，我假设肠道DC已经损害了HIV介导的Toll样受体（TLR）信号传导，从而导致慢性进行性感染个体中T细胞归巢至小肠的功能障碍。在此应用程序中，我打算：1。使用细胞因子分泌和T细胞杀伤的新测定法确定进行性和控制性感染患者中HIV特异性肠道粘膜CD 8 + T细胞的频率和功能能力，2.通过评估E-钙粘蛋白与抑制性受体KLRG 1结合对HIV特异性CD 8 + 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产生视黄酸中的作用以及视黄酸对T细胞肠道归巢受体表达的影响。 相关性（参见说明）：人体的大多数免疫细胞位于胃肠道，在HIV感染期间，该区域非常活跃。然而，HIV在肠道中的影响仍然没有完全研究。我们正在开发新的、最先进的技术，以更好地评估进行性HIV疾病患者肠道中的免疫系统，以及能够在没有药物的情况下控制感染的独特个体。这些研究将提供有助于开发更有效的艾滋病毒疗法和疫苗的见解。

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.