Intestinal cytokine&T cell homeostasis in SIV infection

抗逆转录病毒疗法（ARV）在HIV-1感染者中的疗效是通过病毒抑制来确定的， 恢复外周血中的CD 4 +T细胞数量，其仅占外周血中总淋巴细胞的2%。 淋巴细胞主要分布在胃肠道，而肠相关淋巴组织（GALT）则含有>90%的淋巴细胞。CD 4 +T细胞的动力学 抗逆转录病毒治疗后GALT的细胞恢复和功能尚未完全确定。我们的初步结果显示， 治疗期间SIV感染动物肠道CD 4 <$T细胞的适度但不完全的恢复和功能。我们 提出肠道T淋巴细胞亚群组成的改变（CD 8 + T细胞的患病率增加）， 和炎性细胞因子如TNF α）在原发性SIV感染中的CD 4 + T细胞耗竭后可能具有 在抗逆转录病毒治疗期间对肠道CD 4 +T细胞的恢复产生负面影响。免疫激活和炎症 细胞因子如TNF 0 - 1可能导致CD 4 + T细胞恢复延迟。本报告的总体目标 应用是开发策略以改善或加速HIV感染期间GALT中的CD 4 +T细胞恢复， 通过使用SIV感染的恒河猴模型来确定CD 4 + T细胞再增殖的潜在机制。那里 有三个具体目标。(1)为了确定TNFo_抑制剂RDP 58对肠道CD 4 ~ T细胞恢复的影响， PMPA期间SIV感染恒河猴的T细胞功能、T细胞稳态、细胞周期和病毒抑制 抗病毒治疗治疗将在病毒感染的原发或慢性阶段和纵向空肠 分析活检和外周血样品的CD 4 +T细胞再增殖和功能，细胞周期的变化， 细胞凋亡水平、病毒抑制和基因组多样性的进化。(2)为了确定CD 8？T细胞的作用， 耗竭对CD 4 + T细胞亚群的再增殖和功能以及肠道T细胞稳态和病毒抑制的影响 以及接受治疗的SIV感染恒河猴GALT的衰变动力学和基因组多样性。本研究将 研究了在SIV感染的猕猴中，CD 8 + T细胞在杀死生产性感染细胞中的作用， 有效的抗逆转录病毒疗法(3)为了检测SIV诱导的肠道CD 4 +T细胞耗竭和CD 4 + T细胞减少的进展， 通过基因表达分析治疗期间的T细胞恢复。GALT基因表达谱的检测 SIV感染的动物在接受和不接受治疗的情况下将检测到感染中涉及的细胞和分子机制 相关的病理生理过程。拟议的研究可能会提供深入了解CD 4 <$T细胞的机制， SIV感染期间的消耗和随后ARV联合后GALT中的CD 4 + T细胞恢复 免疫调节剂或CD 8 + T细胞耗竭。

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 TNFa) 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 TNFo_ 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 TNFo_ 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 ¿T 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.