HIV reservoir and CD4 repopulation in gut lymphoid tissue

描述（由申请方提供）：肠道相关淋巴组织（GALT）包含体内大部分淋巴组织，是人类免疫缺陷病毒-1（HIV）感染中病毒复制和记忆性CD 4 + T细胞严重耗竭的重要部位。HAART患者表现出不完全的病毒抑制，GALT中CD 4 + T细胞的恢复明显慢于外周血，这与持续的免疫激活相关。在治疗过程中，GALT中慢性免疫激活和HIV持续存在的机制尚未完全确定。修订后的竞争性更新申请的总体目标是确定HAART期间导致HIV感染患者GALT慢性免疫激活和病毒持续存在的肠道致病机制。我们假设GALT的慢性免疫激活是由于HAART期间HIV感染患者肠上皮更新受损、特异性CD 4 + T细胞亚群丢失和残留病毒复制所致。有三个具体目标：在有或没有HAART的HIV感染患者中，我们将（1）确定GALT与外周血中HIV复制动力学和病毒基因组多样性。(2)研究肠上皮屏障更新受损和绒毛-隐窝轴沿着细胞成熟/分化缺陷的分子机制。(3)研究Th 17 CD 4 + T细胞的流行率、免疫表型和功能，Th 17 CD 4 + T细胞是粘膜免疫防御的关键组成部分。该提案利用了我们在HIV感染的肠道致病性研究方面的经验，我们在患者招募和纵向肠道粘膜研究方面的成功，粘膜免疫学，流式细胞术，基因表达分析和分子病毒学方面的专业知识，以及我们合作者在HIV基因组分析和HIV患者护理方面的专业知识。拟议的研究将提供深入了解慢性免疫激活与肠道粘膜免疫系统受损恢复和HIV感染中病毒持续存在之间联系的机制。这些研究的结果将有助于阐明预防艾滋病毒疾病的新相关因素，并可能影响改进疫苗和治疗方法的发展。公共卫生相关性：尽管进行了治疗，但人体免疫缺陷病毒（HIV）并没有完全从体内清除。我们将研究肠道组织在HIV感染持续性中的作用。由于肠道组织含有人体的大部分免疫细胞，持续的艾滋病毒感染会导致消化和免疫功能严重受损，并可能增加发展为艾滋病的速度。

DESCRIPTION (provided by applicant): Gut associated lymphoid tissue (GALT) harbors the majority of lymphoid tissue in the body and is an important site for viral replication and severe depletion of memory CD4+ T cells in human immunodeficiency virus-1 (HIV) infection. Patients on HAART display incomplete viral suppression and significantly slower restoration of CD4+ T cells in GALT than in peripheral blood and this correlates with persistent immune activation. The mechanisms contributing to chronic immune activation and HIV persistence in GALT during therapy have not been fully defined. The overall objective of this revised competitive renewal application is to determine the mechanisms of enteropathogenesis that contribute to chronic immune activation and viral persistence in GALT of HIV infected patients during HAART. We hypothesize that chronic immune activation in GALT is due to impaired gut epithelium renewal, loss of specific CD4+ T cell subsets, and residual viral replication in HIV infected patients during HAART. There are 3 specific aims: In HIV infected patients with or without HAART, we will (1) determine HIV replication dynamics and viral genomic diversity in GALT compared to peripheral blood. (2) investigate the molecular mechanisms of impaired renewal of the intestinal epithelial barrier and defects in cell maturation/differentiation along the villus-crypt axis. (3) investigate the prevalence, immunophenotype, and function of Th17 CD4+ T cells, a critical component of mucosal immune defense. The proposal capitalizes on our experience in enteropathogenic studies of HIV infection, our success in enrollment and longitudinal gut mucosal studies in patients, expertise in mucosal immunology, multicolor flow cytometry, gene expression analysis, and molecular virology, as well as the expertise of our collaborators in HIV genomic analysis and HIV patient care. The proposed studies will provide insights into the mechanisms that link chronic immune activation to impaired restoration of the gut mucosal immune system and viral persistence in HIV infection. Findings from these studies will be valuable in the elucidation of novel correlates of protection against HIV disease and may impact the development of improved vaccine and therapeutic approaches. PUBLIC HEALTH RELEVANCE: Despite therapy, human immunodeficiency virus (HIV) is not completely eliminated from the body. We will examine the role of intestinal tissue in the persistence of HIV infection. Since the intestinal tissues contain most of the body's immune cells, persistent HIV infection leads to severe impairment of both digestive and immune function and may increase the rate of progression to AIDS.