Pathogenesis of intestinal dysfunction in simian AIDS

猿猴艾滋病肠道功能障碍的发病机制

• 批准号: 7493919
• 负责人: Satya Dandekar
• 金额: $ 1.6万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7493919
• 关键词: Acquired Immunodeficiency Syndrome; Adenine; Affect; Animal Model; Animals; Architecture; Autologous; Biopsy; Bromodeoxyuridine; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell Death; Cell Proliferation; Cells; Characteristics; Chronic; Color; Development; Disease; Disruption; Epithelial; Evaluation; Flow Cytometry; Functional disorder; Funding; Gene Expression; Genes; Genomics; Goals; Growth; Gut associated lymphoid tissue; HIV; HIV-1; Highly Active Antiretroviral Therapy; Homeostasis; Homing; Image; Immune; Immune system; Immunophenotyping; In Situ Hybridization; In Vitro; Individual; Infection; Inflammation; Inflammatory Response; Intestines; Invasive; Kinetics; Label; Lead; Lymph Node Tissue; Lymphocyte; Macaca; Macaca mulatta; Maintenance; Maps; Measures; Memory; Mesentery; Methodology; Microarray Analysis; Modeling; Molecular; Molecular Profiling; Monitor; Mucous Membrane; Natural regeneration; Normal Range; Nucleosides; Nutrient; Pathogenesis; Patients; Pattern; Peripheral; Phenotype; Polymerase Chain Reaction; Population; Principal Investigator; Process; RNA; Range; Regulation; Reporting; Research Personnel; Research Proposals; Residual state; Reverse Transcriptase Inhibitors; SIV; Sampling; Severities; Simian Acquired Immunodeficiency Syndrome; Site; Stimulus; Structure; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Time; Tissue Sample; United States National Institutes of Health; Vaccines; Viral; Viral Load result; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; Week; antiretroviral therapy; base; day; design; experience; in vivo; injury and repair; insight; jejunum; lymph nodes; memory CD4 T lymphocyte; molecular imaging; mucosal site; peripheral blood; phosphonate; pinacolyl methylphosphonic acid; programs; repaired; response; restoration; systemin; trafficking

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.

抗逆转录病毒疗法（ART）在HIV-1感染个体中的疗效是通过恢复来确定的 外周血CD4+ T细胞数量和病毒抑制。但是，外周血仅占2％ 体内总淋巴细胞的。相反，肠道相关的淋巴组织（Galt）港口> 80％ 体内的淋巴细胞。我们先前的研究表明，严重的CD4+ T细胞耗竭发生在 初次HIV感染期间的GALT和GALT中的CD4+ T细胞修复量适中且比较缓慢 在艺术期间进行外围血。 galt中的这些变化没有充分反映在外周血中 分析。 ART后Galt中CD4+ T细胞修复和功能的动力学和机制具有 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 与周围血液相比，研究肠粘膜免疫系统的优秀动物模型 车厢。该研究建议的总体目的是检查病毒的抑制 肠粘膜免疫系统恢复的复制和动力学和机制 与恒河神淋巴结和外周淋巴结中的猕猴开始艺术相比 （PMPA和FTC的组合）在原发性或慢性SIV感染期间。 我们的假设是，在治疗过程中，Galt中CD4+ T细胞的缓慢恢复可以归因于 在SIV感染和 这可能无法充分支持CD4+ T细胞向肠粘膜归入的生存和维持。 SIV模型中的纵向评估将导致机制的表征和关系 在Galt中的CD4+ T细胞恢复之间，外周血和淋巴结区室（外周和 那些排干的粘膜部位）。有3个具体目标。在恒河猕猴中发起艺术 或慢性SIV感染，（1）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）至 确定galt微环境中CD4+ T细胞的归巢和存活，（3） 与肠粘膜免疫系统恢复有关的分子过程。该提案大写 我们在SIV模型中的肠病研究经验，多色流式细胞术专业知识，体内 分子成像，自体T细胞转移和基因表达方法。提出的研究 承诺将有价值的见解对受损的肠道微环境对病毒的影响的影响 与粘膜和外周淋巴相比，肠粘膜免疫系统的抑制和恢复 GALT中病理生理过程的节点室和分子基础。