Role of macrophages in HIV Lipoatrophy

巨噬细胞在 HIV 脂肪萎缩中的作用

• 批准号: 7903933
• 负责人: Cecilia M. Shikuma
• 金额: $ 32.13万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903933
• 关键词: AIDS clinical trial group; Acquired Immunodeficiency Syndrome; Address; Adipocytes; Adipose tissue; Anti-Retroviral Agents; Apoptosis; Biopsy; Blood Circulation; CCL2 gene; CD14 gene; Cells; Clinical Research; Clinical Trials; Control Groups; Cross-Sectional Studies; DNA; Data; Development; Gene Expression; HIV; HIV Infections; IL6 gene; Immunologics; Infiltration; Inflammatory; Laboratories; Laboratory Research; Link; Lipoatrophy; Lymphocyte; Measures; Mitochondria; Mitochondrial DNA; Nucleosides; Oxidative Phosphorylation; Pathogenesis; Patients; Pattern; Peripheral Blood Mononuclear Cell; Play; Proteins; Regimen; Reporting; Research; Research Personnel; Reverse Transcriptase Inhibitors; Role; Small Inducible Cytokine A3; Source; Stavudine; Tenofovir; Testing; Thigh structure; Time; Zidovudine; abacavir; arm; base; cohort; cytokine; macrophage; mitochondrial dysfunction; monocyte; programs

DESCRIPTION (provided by applicant): The causative link between nucleoside reverse transcriptase inhibitor (NRTI)-induced mitochondrial dysfunction and the development of HIV lipoatrophy is now well established. However, host immunologic and HIV virologic factors may contribute to its pathogenesis. We plan to assess their contribution through our central hypothesis that monocytes/macrophages (M/MOs) and HIV infection of such cells play key supporting roles in the pathogenesis of HIV lipoatrophy. Pro-inflammatory cytokines are increased in adipose tissue of lipoatrophic subjects. New data from several research laboratories including our own suggest 1) that adipose tissue M/MO levels are also increased in lipoatrophy and that 2) these M/MOs may be responsible for the high levels of cytokines in such adipose tissue. In a 5 cohort cross-sectional study (n=15/cohort), we propose to verify the increase in adipose tissue M/MOs in lipoatrophic subjects on zidovudine (ZDV)- or stavudine (d4T)-containing antiretroviral (ARV) regimens in comparison to 4 control groups (non-lipoatrophic patients on similar regimens, ARV-na'ive patients, subjects on Tenofovir- and/or Abacavir-containing regimens and HIV-seronegative controls). By assessing cytokines separately in adipocyte, pre-adipocyte and macrophage cellular components, we propose to establish that macrophages are the predominant source of cytokines in lipoatrophic subjects. We will expore the relationships that exist between adipose tissue M/MOs, cytokines, parameters of mitochondrial dysfunction and apoptosis. Finally, we believe that M/MO infiltration is enhanced by HIV infection of such cells in the bloodstream. We will confirm our recent report that lipoatrophy is associated with high levels of HIV infection (HIV DNA) within peripheral blood mononuclear cell (PBMC), and test the hypothesis that this high HIV DNA is found predominantly within the M/MO fraction of PBMCs rather than within lymphocytes. We will conduct these assessments not only in our local cohort but within serially banked PBMCs from selected subjects (n=100) who participated in AIDS Clinical Trials Group (ACTG) A5095, a recently completed large multi-center ARV trial in ARV-naive subjects. The attractiveness of this cohort lies in the ability to objectively identify lipoatrophy through change over time in arm and thigh circumferences. We are particularly well suited to undertake these studies as our research team combines clinical research expertise in HIV lipoatrophy with specific laboratory competency in adipose tissue-, mitochondrial- and M/MO-related research.

描述（由申请人提供）：核苷逆转录酶抑制剂（NRTI）诱导的线粒体功能障碍与HIV脂肪萎缩的发展之间的致病联系。但是，宿主免疫和HIV病毒学因素可能有助于其发病机理。我们计划通过我们的中心假设评估它们的贡献，即这种细胞的单核细胞/巨噬细胞（M/MOS）和HIV感染在HIV脂肪肉芽病的发病机理中起着关键的支持作用。脂肪营养受试者的脂肪组织中促炎性细胞因子增加。包括我们自己的几个研究实验室的新数据。1）脂肪植物中的脂肪组织M/MO水平也有所增加，2）这些M/MOS可能是这种脂肪组织中高水平的细胞因子的原因。在一项5个队列横截面研究（n = 15/队列）中，我们建议验证Zidovudine（ZDV）（ZDV）或Stavudine（d4T） - 含4个对照组的患者（非对照组的患者）在ZIDOVUDINE（ZDV）上的脂肪组织M/MOS的增加（ZDV）（ZDV）（ZDV）（D4T）（D4T）的增加在替诺福韦和/或含阿巴卡维尔的方案和艾滋病毒的控制方案上）。通过在脂肪细胞，脂肪细胞和巨噬细胞成分中分别评估细胞因子，我们建议确定巨噬细胞是脂肪营养受试者中细胞因子的主要来源。我们将阐明脂肪组织M/MOS，细胞因子，线粒体功能障碍的参数和凋亡之间存在的关系。最后，我们认为M/MO浸润通过血液中此类细胞的HIV感染增强。我们将确认我们最近的报道，脂肪植物与外周血单核细胞（PBMC）内的高水平的HIV感染（HIV DNA）有关，并检验假说，即这种高HIV DNA主要在PBMC的M/MO分数中发现，而不是在PBMC中，而不是在淋巴细胞中。我们将不仅在本地队列中，而且将在参加AIDS临床试验组（ACTG）A5095的选定受试者（n = 100）的串行银行PBMC中进行这些评估。该队列的吸引力在于能够通过随着时间的流逝和大腿圆周的时间变化而客观地识别脂肪植物的能力。我们的研究团队将HIV脂肪植物的临床研究专业知识与脂肪组织，线粒体和M/MO相关的研究相结合，我们特别适合进行这些研究。