SIV Cardiomyopathy: Pathogenesis and Prevention

描述（由申请人提供）： 艾滋病毒相关的心脏病理学越来越多地被认为是慢性艾滋病毒感染的患者，他们可以生存下来，过上有意义的生活。HIV相关性心肌病是慢性HIV感染最常见的心脏特异性表现之一，在6-12%死于AIDS的患者中观察到。然而，心血管受累已不仅仅是一种病理学上的好奇心，而是一个重要的发病原因，因为艾滋病毒感染者的寿命更长，生活更有成效。HAART治疗的使用越来越多，有助于揭示HIV相关的心脏受累倾向。尽管认识有所增加，但HIV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。我们实验室先前的工作已经描述了时间进程、CIM计数的作用以及猿类艾滋病的多形性心脏表现。这项工作表明，在确定那些风险增加的患者时，需要考虑病毒和宿主因素，并建立一个一致的、可重复的心脏受累模型，以供进一步研究。我们已经确定嗜巨噬细胞的SIV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受累病例中定位于心肌，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细胞。由活化的巨噬细胞产生的TNF α介导心肌细胞中NOS 2的上调和Fas（CD 95）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-κ B NOS 2表达）和不可逆的心肌损伤（Fas-FasL介导的细胞凋亡）中起着重要的机制作用。此外，淋巴细胞浸润通常在血管周围，并与冠状动脉血管病变相关，其特征为内皮活化、平滑肌增殖和血栓闭塞，导致急性缺血性损伤。这些病理学特征反映在肺中，在肺中观察到淋巴细胞性间质性肺炎和肺血管病变，并导致右心室功能障碍增加。我们计划探索导致SIV传播进入心肌（SIV向心性）和SIV介导的损伤（心脏毒力）的宿主和病毒因素。确定的机制将作为探索预防慢性SIV感染心脏受累的特定策略的先决条件。

DESCRIPTION (provided by applicant): HIV associated cardiac pathology is being recognized increasingly as patients with chronic HIV infection who 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 CIM 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 up-regulation 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-kappaB 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.