PATHOGENESIS OF INTESTINAL DYSFUNCTION IN SIMIAN AIDS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 抗逆转录病毒疗法(ART)对HIV-1感染者的疗效取决于外周血中CD4+T细胞数量的恢复和病毒抑制。然而，外周血液只占体内淋巴细胞总数的2%。相比之下，肠道相关淋巴组织(GALT)容纳了体内80%的淋巴细胞。我们以前的研究表明，在初次HIV感染期间，GALT中会发生严重的CD4+T细胞耗竭，与ART期间的外周血相比，GALT中的CD4+T细胞恢复缓慢而温和。GALT的这些变化在外周血液分析中没有得到充分的反映。ART术后GALT中CD4+T细胞恢复和功能的动力学和机制尚未完全确定。猴免疫缺陷病毒(SIV)感染恒河猴为研究肠道粘膜免疫系统提供了一个良好的动物模型。本研究建议的总体目标是通过比较肠粘膜、外周淋巴结和外周血(PMPA和FTC的组合)在初发SIV感染期间对恒河猴肠道粘膜免疫系统和功能的抑制作用以及肠道粘膜免疫系统和功能恢复的动力学和机制。我们的假设是，治疗过程中GALT中CD4+T细胞的缓慢恢复可以归因于SIV感染早期肠粘膜组织功能的破坏，这可能不足以支持归巢于肠粘膜的CD4+T细胞的生存和维持。在SIV模型中的纵向评估将导致描述GALT、外周血和淋巴结室(外周和那些引流粘膜部位)中CD4+T细胞恢复的机制和关系。有三个具体目标。在原发或慢性SIV感染期间启动抗逆转录病毒治疗的恒河猴中，(1)确定SIV复制和基因组多样性的抑制，以及GALT中CD4+T细胞恢复的动力学，比较外周血和淋巴结；(2)确定CD4+T细胞在GALT微环境中的归巢和存活；以及(3)研究参与肠道粘膜免疫系统恢复的分子过程。该提案利用了我们在SIV模型中的肠道病理学研究方面的经验，以及在多色流式细胞术、体内分子成像、自体T细胞转移和基因表达方法方面的专业知识。与粘膜和外周淋巴结室相比，肠道微环境受损对肠道黏膜免疫系统病毒抑制和修复的影响，以及GALT病理生理过程的分子基础，这些研究有望提供有价值的见解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The efficacy of antiretroviral therapy (ART) in HIV-1 infected individuals is determined by restoration of peripheral blood CD4+ T cell numbers and viral suppression. However, peripheral blood represents only 2% of the total lymphocytes in the body. In contrast, gut associated lymphoid tissue (GALT) harbors 80% of the lymphocytes in the body. Our previous studies showed that severe CD4+ T cell depletion occurs in GALT during primary HIV infection and that CD4+ T cell restoration in GALT is modest and slow compared to peripheral blood during ART. These changes in GALT are not adequately reflected in peripheral blood analysis. The kinetics and mechanisms of CD4+ T cell restoration and function in GALT following ART have not been fully determined. Simian immunodeficiency virus (SIV) infected rhesus macaques provide an excellent animal model to study the gut mucosal immune system in comparison to peripheral blood compartment. The overall objective of this research proposal is to examine the suppression of viral replication and kinetics and mechanisms of restoration of gut mucosal immune system and function in comparison to mucosal and peripheral lymph nodes and peripheral blood in rhesus macaques starting ART (combination of PMPA and FTC) during primary or chronic SIV infection. Our hypothesis is that slow restoration of CD4+ T cells in GALT during therapy can be attributed to the disruption of the functional organization of the gut mucosal tissue occurring very early in SIV infection and this may not adequately support survival and maintenance of the CD4+ T cells homing to gut mucosa. Longitudinal evaluation in the SIV model will lead to characterization of the mechanisms and relationship between CD4+ T cell restoration in GALT, peripheral blood, and lymph node compartments (peripheral, and those draining mucosal sites). There are 3 specific aims. In rhesus macaques initiating ART during primary or chronic SIV infection, (1) to determine suppression of SIV replication and genomic diversity, and the kinetics of CD4+ T cell restoration in GALT in comparison to peripheral blood and lymph nodes; (2) to determine the homing and survival of CD4+ T cells in the GALT microenvironment and (3) to investigate the molecular processes involved in the restoration of gut mucosal immune system. The proposal capitalizes on our experience in enteropathogenic studies in the SIV model, expertise in multi-color flow cytometry, in vivo molecular imaging, autologous T cell transfer and gene expression methodologies. The proposed studies promise to provide valuable insights into the impact of impaired gut microenvironment on the viral suppression and restoration of gut mucosal immune system compared to mucosal and peripheral lymph node compartments, and molecular basis of pathophysiologic processes in GALT.