Pathogenesis of intestinal dysfunction in simian AIDS

抗逆转录病毒疗法（ART）在HIV-1感染者中的疗效是通过恢复HIV-1感染者的 外周血CD4 + T细胞数量和病毒抑制。然而，外周血仅占2%， 体内淋巴细胞总数的百分之一。相反，肠相关淋巴组织（GALT）含有> 80%的 体内的淋巴细胞。我们以前的研究表明，严重的CD4 + T细胞耗竭发生在 GALT中的CD4 + T细胞恢复是适度和缓慢的， GALT的这些变化不能充分反映在外周血中， 分析. ART后GALT中CD4 + T细胞恢复和功能的动力学和机制已被证实。 尚未完全确定。猿猴免疫缺陷病毒（SIV）感染的恒河猴提供了一种免疫抑制剂， 与外周血相比，这是研究肠道粘膜免疫系统的极佳动物模型 车厢这项研究计划的总体目标是检查病毒的抑制， 复制和动力学和机制的恢复肠道粘膜免疫系统和功能， 开始ART的恒河猴中粘膜和外周淋巴结以及外周血的比较 （PMPA和FTC的组合）在原发性或慢性SIV感染期间。 我们的假设是，治疗期间GALT中CD4 + T细胞的缓慢恢复可归因于 在SIV感染的极早期发生的肠粘膜组织的功能组织的破坏， 这可能不足以支持归巢到肠粘膜的CD4 + T细胞的存活和维持。 SIV模型中的纵向评估将导致对机制和关系的表征 GALT、外周血和淋巴结隔室（外周和外周）中CD4 + T细胞恢复之间的关系 那些引流粘膜部位）。有三个具体目标。在初次接受ART治疗的恒河猴中 或慢性SIV感染，（1）以确定SIV复制和基因组多样性的抑制， 与外周血和淋巴结相比，GALT中CD4 + T细胞恢复的动力学;（2） 确定CD4 + T细胞在GALT微环境中的归巢和存活，以及（3）研究CD4 + T细胞在GALT微环境中的表达。 参与肠粘膜免疫系统恢复的分子过程。该提案利用了 我们在SIV模型肠道致病性研究方面的经验，多色流式细胞术的专业知识，体内 分子成像、自体T细胞转移和基因表达方法学。拟议的研究 有望为受损的肠道微环境对病毒的影响提供有价值的见解。 与粘膜和外周淋巴相比，肠粘膜免疫系统的抑制和恢复 结室和GALT病理生理过程的分子基础。

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.