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.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。随着慢性艾滋病毒感染患者能够存活并过上有意义的生活，艾滋病毒相关的心脏病理越来越被认识到。HIV相关心肌病是慢性HIV感染最常见的心脏特异性表现之一，在6-12%死于艾滋病的患者中观察到。然而，心血管疾病的出现已经不仅仅是一种病理上的好奇，而是作为一种重要的发病原因，因为感染艾滋病毒的个体寿命更长，生活更有成效。HAART治疗的增加使用有助于揭示HIV相关的心脏受累倾向。尽管认识有所提高，但艾滋病毒相关心脏病的危险因素、发病机制和所需的具体治疗仍然未知。恒河猴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。我们实验室之前的工作已经描述了猿类艾滋病的时间过程、CD4计数的作用和心脏的多形性表现。这项工作表明，在确定风险增加的人群时，需要考虑病毒和宿主因素，并为进一步的研究创建一个一致的、可重复的心脏受累模型。我们已经确定SIV嗜巨噬细胞毒株最常与淋巴细胞性心肌炎相关。SIV在大约三分之一的心脏累及病例中定位于心肌，并且当存在时，总是共定位于巨噬细胞谱系的细胞，组织巨噬细胞或心脏树突状细胞。TNFalpha由活化的巨噬细胞产生，介导心肌细胞中NOS2的上调和Fas （CD95）受体的表达，导致心肌细胞凋亡。因此，我们已经证明细胞因子在可逆性左室功能障碍（NF-kappa B NOS2表达增加）和不可逆性心肌损伤（Fas-FasL介导的细胞凋亡）中发挥核心机制作用。此外，淋巴细胞浸润经常发生在血管周围，并与冠状血管病变相关，其特征为内皮活化、平滑肌增生和血栓闭塞，导致急性缺血性损伤。肺淋巴细胞间质性肺炎和肺血管病变也反映了这些病理特征，并导致右室功能障碍加重。我们计划探索导致SIV传播到心肌（SIV的心向性）和SIV介导的损伤（心毒性）的宿主和病毒因素。确定的机制将作为探索慢性SIV感染预防心脏受累的具体策略的先决条件。