Intestinal cytokine&T cell homeostasis in SIV infection

描述(申请人提供)：抗逆转录病毒疗法(ARV)对HIV-1感染者的疗效取决于病毒抑制和外周血中CD4+T细胞数量的恢复，这只占体内淋巴细胞总数的2%；而肠道相关淋巴组织(GalT；)含有90%的淋巴细胞。ARV后GALT中CD4+T细胞恢复和功能的动力学尚未完全确定。我们的初步结果显示，在治疗过程中，SIV感染动物的肠道CD4+T细胞有适度但不完全的恢复和功能。我们认为，在初次SIV感染中，肠道T淋巴细胞亚群组成的改变(CD8+T细胞和炎性细胞因子如TNFpha等炎性细胞因子的增加)可能对ARV期间肠道CD4+T细胞的恢复有负面影响。免疫激活和炎性细胞因子，如肿瘤坏死因子，可能是导致CD4+T细胞恢复延迟的原因之一。这项应用的总体目标是开发策略，以改善或加速HIV感染期间GALT中CD4+T细胞的恢复，并通过使用SIV感染的恒河猴模型确定CD4+T细胞重新繁殖的潜在机制。有三个具体目标。(1)研究PMPA抗病毒治疗过程中，肿瘤坏死因子α抑制剂RDP58对SIV感染恒河猴肠道CD4+T细胞恢复和功能、T细胞动态平衡、细胞周期和病毒抑制的影响。治疗将在病毒感染的初级或慢性阶段开始，并对纵向空肠活检和外周血样进行分析，以了解CD4+T细胞的再繁殖和功能、细胞周期和凋亡水平的变化、病毒抑制和基因组多样性的演变。(2)探讨CD8Vt细胞去除对SIV感染恒河猴肠道T细胞亚群和功能的影响，对SIV感染恒河猴肠道T细胞动态平衡、病毒抑制、病毒衰变动力学和基因组多样性的影响。这项研究将研究在有效的抗逆转录病毒治疗期间，CD8+T细胞在杀死SIV感染猕猴的生产性感染细胞中的作用。(3)通过基因表达分析检测SIV诱导的肠道CD4+T细胞耗竭和恢复的进展情况。检测SIV感染动物GALT基因表达谱将发现感染相关病理生理过程中涉及的细胞和分子机制。这项研究可能对SIV感染过程中CD4+T细胞耗尽的机制以及ARV联合免疫调节剂或CD8+T细胞耗尽后GALT中CD4+T细胞的恢复提供深入的认识。

DESCRIPTION (provided by applicant): Efficacy of antiretroviral therapy (ARV) in HIV-1 infected individuals is determined by viral suppression and restoration of CD4 +T cell numbers in the peripheral blood, which represents only 2% of the total lymphocytes in the body; whereas, the gut associated lymphoid tissue (GALT) harbors >90% of the lymphocytes. The kinetics of CD4 +T cell restoration and function in GALT following ARV has not been fully determined. Our preliminary results showed a modest but incomplete restoration and function of intestinal CD4+T cells in SIV-infected animals during therapy. We propose that the alterations in composition of intestinal T lymphocyte subsets (increased prevalence of CD8+ T cells and inflammatory cytokines such as TNFalpha subsequent to CD4+ T cell depletion in primary SIV infection may have a negative impact on the restoration of intestinal CD4 +T cells during ARV. Immune activation and inflammatory cytokines such as TNFalpha may contribute to the delay in the CD4 + T cell restoration. The overall objective of this application is to develop strategies to improve or accelerate CD4 +T cell restoration in GALT during HIV infection and to identify potential mechanisms of CD4 + T cell repopulation by using the SIV-infected rhesus macaque model. There are three specific aims. (1) To determine the effects of TNFalpha inhibitor, RDP58, on intestinal CD4+ T cell restoration and function, T cell homeostasis, cell cycle stage and viral suppression in SIV-infected rhesus macaques during PMPA antiviral therapy. Therapy will be initiated in the primary or chronic stage of viral infection and longitudinal jejunal biopsy and peripheral blood samples analyzed for CD4+ T cell repopulation and function, changes in cell cycle and levels of apoptosis, viral suppression and evolution of genomic diversity. (2) To determine the effect of CD8 vT cell depletion on repopulation and function of CD4 + T cell subsets and intestinal T cell homeostasis and viral suppression and decay kinetics and genomic diversity in GALT of SIV-infected rhesus macaques receiving therapy. This study will examine the contribution of CD8+ T cells in killing of productively infected cells in SIV infected macaques during potent antiretroviral therapy. (3) To examine the progression of SIV-induced intestinal CD4+T cell depletion and CD4+ T cell restoration during therapy by gene expression analysis. Examination of gene expression profiles in GALT of SIV-infected animals with and without therapy will detect cellular and molecular mechanisms involved in the infection associated pathophysiologic process. The proposed studies may provide insights into mechanisms of CD4+T cell depletion during SIV infection and subsequent CD4+ T cell restoration in GALT following ARV in combination with an immunomodulator or CD8+ T cell depletion.