SIV CARDIOMYOPATHY: PATHOGENESIS AND PREVENTION

SIV 心肌病：发病机制和预防

• 批准号: 7349494
• 负责人: Richard P Shannon
• 金额: $ 13.48万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349494
• 关键词: SIV; CARDIOMYOPATHY; PATHOGENESIS; PREVENTION

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. HIV associated cardiac pathology is being recognized increasingly as patients with chronic HIV infection survive to live productive lives. HIV associated cardiomyopathy is among the most common cardiac specific manifestation of chronic HIV infection and was observed in between 6-12% of patients that succumb to AIDS. However, cardiovascular involvement has emerged as more than a pathologic curiosity, but rather as a significant cause of morbidity as individuals live longer, more productive lives with HIV. Increased use of HAART therapy has served to unmask HIV associated predispositions to cardiac involvement. Despite the increased recognition, the risks factors for, the pathogenesis of, and the specific treatments required in HIV associated cardiac disease remain unknown. The nonhuman primate model of SIV infection in rhesus macaques affords an unparalleled opportunity to study these critical features. Prior work from our laboratory has characterized the time course, the role of CD4 counts, and the pleomoprhic cardiac manifestations in simian AIDS. The work has demonstrated the need to consider both viral and host factors in identifying those at increased risk and to create a consistent, reproducible model of cardiac involvement for further investigation. We have determined that macrophage-tropic strains of SIV are most commonly associated with lymphocytic myocarditis. SIV is localized to the myocardium in approximately one third of cases of cardiac involvement, and when present, always co-localizes to cells of the macrophage lineage, either tissue macrophages or cardiac dendritic cells. TNFalpha, produced by activated macrophages, mediates both upregulation of NOS2 in cardiac myocytes and the expression of Fas (CD95) receptors leading to cardiac myocyte apoptosis. As such, we have shown that cytokines play a central mechanistic role in both reversible LV dysfunction (increased NF-kappa B NOS2 expression) and irreversible myocardial injury (Fas-FasL mediated apoptosis). In addition, lymphocytic infiltrates are frequently perivascular and associated with coronary vascular lesions characterized by endothelial activation, smooth muscle proliferation, and thrombotic occlusions, leading to acute ischemic injury. These pathological features are mirrored in the lung where lymphocytic interstitial pneumonia and pulmonary vasculopathy are observed and contribute to increased right ventricular dysfunction. We plan to explore both host and viral factors that lead to SIV transmission into the myocardium (SIV cardiotropism) and SIV mediated injury (cardiovirulence). The identified mechanisms will serve as a prerequisite for exploring specific strategies to prevent cardiac involvement in chronic SIV infection.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。随着慢性艾滋病毒感染的患者能够生存生产力，艾滋病毒相关的心脏病理越来越多地被识别。 HIV相关的心肌病是慢性HIV感染最常见的心脏特异性表现之一，在6-12％的屈服于艾滋病的患者中观察到。然而，心血管的参与不仅仅是一种病理性的好奇心，但由于个体寿命更长，艾滋病毒的生产力更高，因此发病的重要原因。 HAART疗法的使用增加已揭露与心脏参与的HIV相关倾向。尽管识别率增加，但艾滋病毒相关心脏疾病所需的风险因素，发病机理和特定疗法仍然未知。 恒河猕猴中SIV感染的非人类灵长类动物模型为研究这些关键特征提供了无与伦比的机会。我们实验室的先前工作表征了时间过程，CD4计数的作用以及院子艾滋病中的Pleomoprhic心脏表现。这项工作表明需要考虑病毒和宿主因素，以确定风险增加的人，并创建一种一致的，可再现的心脏参与模型以进行进一步研究。我们已经确定，SIV的巨噬细胞 - 热带菌株最常见于淋巴细胞心肌炎。在大约三分之一的心脏受累病例中，SIV位于心肌中，并且在存在时始终将其定位于巨噬细胞谱系的细胞，即组织巨噬细胞或心脏树突状细胞。由激活的巨噬细胞产生的TNFALPHA介导心肌细胞中NOS2的上调以及FAS（CD95）受体的表达，导致心肌细胞凋亡。因此，我们已经表明，细胞因子在可逆的LV功能障碍（增加NF-KAPPA B NOS2表达）和不可逆的心肌损伤（FAS-FAS-FASL介导的凋亡）中起着核心机械作用。另外，淋巴细胞浸润通常是血管周围的，与冠状动脉病变有关，其特征是内皮激活，平滑肌增殖和血小板闭塞，导致急性缺血性损伤。这些病理特征在肺中反映在肺部间质性肺炎和肺血管病中，并有助于增加右心室功能障碍。我们计划探索导致SIV传播到心肌（SIV心形）和SIV介导的损伤（心脏动力电阻）的宿主和病毒因素。确定的机制将是探索预防心脏参与慢性SIV感染的特定策略的先决条件。