SIV Cardiomyopathy: Pathogenesis and Prevention

描述(由申请人提供)： 与艾滋病毒相关的心脏病理越来越被认为是慢性艾滋病毒感染的患者，他们活着过着富有成效的生活。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，在死于艾滋病的患者中可观察到6-12%。然而，心血管疾病已经不仅仅是一种病理上的好奇，而是一种重要的致病原因，因为感染艾滋病毒的人可以活得更长、更有成效。HAART治疗的增加有助于揭示HIV相关心脏受累的易感性。尽管人们对艾滋病毒相关心脏病的认识有所增加，但艾滋病毒相关心脏病的风险因素、发病机制和所需的具体治疗仍不清楚。猕猴体内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一个无与伦比的机会。我们实验室以前的工作已经确定了猿猴艾滋病的时间进程、CIM计数的作用以及胸腔出血的心脏表现。这项工作表明，在识别风险增加的人时，需要同时考虑病毒和宿主因素，并为进一步的研究建立一个一致的、可重复的心脏受累模型。我们已经确定，嗜巨噬细胞的SIV菌株最常与淋巴细胞性心肌炎有关。在大约三分之一的心脏受累病例中，SIV定位于心肌，当存在时，总是共定位于巨噬细胞系的细胞，无论是组织巨噬细胞还是心脏树突状细胞。由激活的巨噬细胞产生的肿瘤坏死因子α，既介导心肌细胞NOS2的上调，又介导Fas(CD95)受体的表达，导致心肌细胞的凋亡。因此，我们已经证明细胞因子在可逆性左心功能障碍(核因子-kappaB NOS2表达增加)和不可逆性心肌损伤(Fas-FasL介导的细胞凋亡)中都起着中心机制的作用。此外，淋巴细胞渗入常位于血管周围，并与冠状动脉血管病变相关，表现为内皮细胞活化、平滑肌增殖和血栓性闭塞，导致急性缺血性损伤。这些病理特征反映在肺中，观察到淋巴细胞性间质性肺炎和肺血管病变，并导致右心功能不全的增加。我们计划探索导致SIV传播到心肌(SIV向心性)和SIV介导的损伤(心脏毒力)的宿主和病毒因素。已确定的机制将作为探索防止慢性SIV感染涉及心脏的具体策略的先决条件。

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.