PATHOGENESIS OF INTESTINAL DYSFUNCTION IN SIMIAN AIDS

该子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心赠款提供。次级项目的主要支助 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 为子项目列出的总成本可能 表示子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 抗逆转录病毒疗法（ART）在HIV-1感染者中的疗效取决于外周血CD 4 + T细胞数量的恢复和病毒抑制。然而，外周血仅占体内淋巴细胞总数的2%。相比之下，肠道相关淋巴组织（GALT）拥有体内80%的淋巴细胞。我们以前的研究表明，严重的CD 4 + T细胞耗竭发生在GALT在原发性HIV感染和GALT中的CD 4 + T细胞的恢复是温和和缓慢的外周血相比，在ART。GALT的这些变化没有充分反映在外周血分析。ART后GALT中CD 4 + 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）感染的恒河猴为研究肠道粘膜免疫系统提供了一个很好的动物模型。本研究提案的总体目标是检查在原发性或慢性SIV感染期间开始ART（PMPA和FTC组合）的恒河猴中，与粘膜和外周淋巴结和外周血相比，对病毒复制的抑制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，治疗期间GALT中CD 4 + T细胞的缓慢恢复可归因于SIV感染早期发生的肠粘膜组织功能组织的破坏，这可能不足以支持归巢至肠粘膜的CD 4 + T细胞的存活和维持。SIV模型中的纵向评价将导致GALT、外周血和淋巴结隔室（外周和引流粘膜部位）中CD 4 + T细胞恢复之间的机制和关系的表征。有三个具体目标。在原发或慢性SIV感染期间启动ART的恒河猴中，（1）确定与外周血和淋巴结相比，GALT中SIV复制和基因组多样性的抑制，以及CD 4 + T细胞恢复的动力学;（2）确定CD 4 + T细胞在GALT微环境中的归巢和存活，以及（3）探讨肠道黏膜免疫系统恢复的分子机制。该提案利用了我们在SIV模型肠道致病性研究方面的经验，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学方面的专业知识。拟议的研究有望提供有价值的见解受损的肠道微环境对病毒的抑制和肠道粘膜免疫系统的恢复相比，粘膜和外周淋巴结隔室，和GALT的病理生理过程的分子基础的影响。

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.