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Intestinal cytokine&T cell homeostasis in SIV infection

肠细胞因子

基本信息

批准号：
7163484
负责人：
Satya Dandekar
金额：
$ 38.38万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-03-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7163484
关键词：
Adenine Affect Animal Model Animals Antibodies Antigens Antiviral Therapy Apoptosis Biopsy Blood Blood specimen Branched DNA Signal Amplification Assay CD3 Antigens CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Count Cell Cycle Cell Cycle Stage Cells Chronic Development Enteral Evolution Exposure to Flow Cytometry Gene Expression Genes Genomics Gut associated lymphoid tissue HIV HIV Enteropathy HIV Infections HIV-1 Highly Active Antiretroviral Therapy Homeostasis Homing Immune Immunomodulators Immunophenotyping In Situ Hybridization In Vitro Individual Infection Inflammatory Intestinal Mucosa Intestines Kinetics Lymphocyte Macaca Macaca mulatta Maps Microarray Analysis Mitogens Modeling Molecular Molecular Profiling Monitor Nucleosides Numbers Patients Peripheral Phenotype Population Prevalence Process Production RDP58 Reverse Transcriptase Inhibitors SIV Staging T-Cell Depletion T-Lymphocyte T-Lymphocyte Subsets TNF gene Tissues Vaccines Viral Viral Load result Viral Pathogenesis Virus Diseases Week antiretroviral therapy cDNA Arrays cytokine improved inhibitor/antagonist insight killings lymph nodes peripheral blood phosphonate pinacolyl methylphosphonic acid response restoration

项目摘要

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.

HIV-1 感染者抗逆转录病毒治疗 (ARV) 的疗效取决于病毒抑制和外周血中CD4+T细胞数量恢复，仅占淋巴细胞总数的2% 身体;而肠道相关淋巴组织 (GALT) 则含有 >90% 的淋巴细胞。 CD4+T的动力学 ARV 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感染 SIV 的动物肠道 CD4 ¿T 细胞的恢复和功能适度但不完全。我们提出肠道 T 淋巴细胞亚群组成的改变（CD8+ T 细胞的患病率增加）原发性 SIV 感染中 CD4+ T 细胞耗竭后的炎症细胞因子（例如 TNFa）可能会产生 ARV期间肠道CD4+T细胞恢复的负面影响。免疫激活和炎症 TNFo_等细胞因子可能会导致CD4+T细胞恢复延迟。本次活动的总体目标该应用的目的是制定策略，以改善或加速 HIV 感染期间 GALT 中 CD4 + T 细胞的恢复，以及通过使用 SIV 感染的恒河猴模型来确定 CD4 + T 细胞再增殖的潜在机制。那里是三个具体目标。 (1) 确定TNFo_抑制剂RDP58对肠道CD4 ¿T细胞恢复的影响 PMPA 期间感染 SIV 的恒河猴的功能、T 细胞稳态、细胞周期阶段和病毒抑制抗病毒治疗。治疗将在病毒感染的初级或慢性阶段和纵向空肠开始活检和外周血样本分析 CD4 + T 细胞的增殖和功能、细胞周期的变化和细胞凋亡、病毒抑制和基因组多样性进化的水平。 (2) 测定CD8 ¿T细胞的作用 CD4 + T 细胞亚群的再生和功能以及肠道 T 细胞稳态和病毒抑制的耗竭以及接受治疗的 SIV 感染恒河猴 GALT 的衰变动力学和基因组多样性。这项研究将检查 CD8+ T 细胞在杀死 SIV 感染的猕猴中有效感染细胞的过程中的贡献有效的抗逆转录病毒治疗。 (3) 检查SIV诱导的肠道CD4+T细胞耗竭和CD4+的进展通过基因表达分析治疗期间 T 细胞恢复。 GALT 中基因表达谱的检查无论是否接受治疗，感染 SIV 的动物都会检测到感染所涉及的细胞和分子机制相关的病理生理过程。拟议的研究可能有助于深入了解 CD4 ¿T 细胞的机制 SIV 感染期间的耗竭以及随后 ARV 联合治疗后 GALT 中 CD4 + T 细胞的恢复免疫调节剂或 CD8+ T 细胞耗竭。