Intestinal cytokine&T cell homeostasis in SIV infection

描述（由申请人提供）：抗逆转录病毒疗法（ARV）在HIV-1感染个体中的疗效是通过病毒抑制和外周血中CD 4 +T细胞数量的恢复来确定的，外周血仅占体内总淋巴细胞的2%;而肠道相关淋巴组织（GALT）含有>90%的淋巴细胞。抗逆转录病毒治疗后GALT中CD 4 +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感染动物肠道CD 4 +T细胞的恢复和功能适度但不完全。我们认为，肠道T淋巴细胞亚群组成的改变（CD 8 + T细胞和炎性细胞因子如TNF α在原发性SIV感染中CD 4 + T细胞耗竭后的流行率增加）可能对ARV期间肠道CD 4 +T细胞的恢复产生负面影响。免疫激活和炎性细胞因子如TNF α可能导致CD 4 + T细胞恢复延迟。本申请的总体目标是开发改善或加速HIV感染期间GALT中CD 4 +T细胞恢复的策略，并通过使用SIV感染的恒河猴模型来鉴定CD 4 + T细胞再增殖的潜在机制。有三个具体目标。(1)探讨TNF α抑制剂RDP 58在PMPA抗病毒治疗过程中对SIV感染恒河猴肠道CD 4 + T细胞恢复和功能、T细胞稳态、细胞周期和病毒抑制的影响。治疗将在病毒感染的原发或慢性阶段开始，并对纵向空肠活检和外周血样本进行CD 4 + T细胞再增殖和功能、细胞周期和细胞凋亡水平变化、病毒抑制和基因组多样性演变分析。(2)确定CD 8 vT细胞耗竭对接受治疗的SIV感染恒河猴的CD 4 + T细胞亚群的再增殖和功能、肠道T细胞稳态、病毒抑制和衰变动力学以及GALT基因组多样性的影响。本研究将探讨在有效的抗逆转录病毒治疗过程中，CD 8 + 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CD 4 +T细胞耗竭和治疗期间CD 4 + T细胞恢复的进展。在SIV感染动物的GALT基因表达谱的检查与治疗和不治疗将检测感染相关的病理生理过程中涉及的细胞和分子机制。拟议的研究可能会提供深入了解SIV感染期间CD 4 +T细胞耗竭的机制，以及ARV联合免疫调节剂或CD 8 + T细胞耗竭后GALT中随后的CD 4 + T细胞恢复。

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.