Myocardial Vulnerability to Ischemia-Induced Dysfunction and Heart Failure: The Impact of HIV/SIV, ART, and Targeted Immunotherapy

总结 人类免疫缺陷病毒（HIV）感染者发生心肌梗死（MI）的风险高1.25至2倍 和心力衰竭（HF）的发病率。冠状动脉缺血和心肌梗死是心力衰竭最常见的原因 一般来说，可能是HIV感染者（PWH）HF的特别重要的原因;我们最近 研究表明，在抗逆转录病毒治疗（ART）的病毒控制下，PWH的心肌 （心肌）损害后MI比人没有艾滋病毒谁有类似的危险因素和冠状动脉解剖。一 这些发现的潜在原因与持续的免疫失调和靶向不当有关。 这些可能使PWH特别容易发病 以及心肌损伤和在MI期间和之后导致的HF。 慢性免疫激活和炎症与PWH的心血管风险增加相关， 这些联系在威尔斯亲王医院比未受感染的人更强。然而，目前尚不清楚艾滋病毒与 免疫激活的异常影响心脏损伤、功能障碍，并最终导致HF， 冠状动脉缺血和MI。单靠观察性研究无法回答这个问题。信息动物 因此，需要模型来（1）确定HIV、ART和相关的免疫失调如何影响 缺血性心脏重塑和导致的HF，和（2）确定免疫调节疗法， 缺血性心脏损伤、功能障碍和HF。在本申请中，我们提出确定以下各项的作用： HIV/猴免疫缺陷病毒（SIV）、ART以及特定淋巴细胞亚群和趋化因子 心肌梗死后不良心脏重塑的因素。我们将使用一种新的缺血再灌注心肌梗死模型， 共同PI-一名心脏病专家和临床/转化研究人员，一名基础科学家， HIV的非人灵长类动物模型-在SIV+猪尾猕猴中成功试点。我们的闭胸MI 模型最接近地反映了当代人类MI和我们的SIV+猪尾猕猴模型 复制HIV相关的免疫反应。这将使我们能够确定艾滋病毒/SIV和ART对 目标1中的MI后心脏结构和功能。在目标2中，我们将进行针对性的CD4+耗竭， CD8 + T细胞，以确定这些亚群在HIV/SIV相关的MI反应中的作用。在目标3中，我们将 施用靶向免疫疗法以阻断T细胞活化/共刺激并抑制外周单核细胞 招募和贩运-免疫调节干预措施可能特别有希望平息 SIV/HIV相关的免疫激活和改善MI后损伤。我们的应用程序高度响应 国家心肺血液研究所（NHLBI）的特别关注通知（NOSI）NOT-HL-19 - 677， 提出探索性和创新性研究以了解HIV相关心血管疾病的申请 疾病我们希望我们的研究将产生新的见解免疫发病机制MI和HF的艾滋病毒和 为今后的努力提供信息，以遏制艾滋病毒感染者的心肌损伤、功能障碍和由此产生的HF。

SUMMARY People with human immunodeficiency virus (HIV) have 1.25- to 2-fold higher risks for myocardial infarction (MI) and heart failure (HF) than people without HIV. Coronary ischemia and MI are the most common causes of HF in general and may be particularly important causes of HF for people with HIV (PWH); we recently demonstrated that PWH with viral control on antiretroviral therapy (ART) have twice the extent of heart muscle (myocardial) damage after MI than people without HIV who had similar risk factors and coronary anatomy. A potential reason for these findings relates to persistent immune dysregulation and improperly targeted inflammation which characterize chronic HIV on ART. These may make PWH especially vulnerable to onset and propagation of MI during ischemia, as well as myocardial damage and resulting HF during and after MI. Chronic immune activation and inflammation are associated with heightened cardiovascular risks for PWH, and these associations are stronger for PWH than uninfected people. However, it is unknown how HIV-related abnormalities in immune activation affect cardiac damage, dysfunction, and ultimately HF resulting from coronary ischemia and MI. Observational studies alone cannot answer this question. Informative animal models are therefore required to (1) determine how HIV, ART, and related immune dysregulation may impact ischemic cardiac remodeling and resulting HF, and (2) identify immunomodulatory therapies that ameliorate ischemic cardiac damage, dysfunction, and HF in HIV. In this application, we propose to determine the roles of HIV/simian immunodeficiency virus (SIV), ART, as well as specific lymphoid cell subsets and chemotactic factors in post-MI adverse cardiac remodeling. We will use a novel model of ischemia-reperfusion MI that our co-PIs – one a cardiologist and clinical/translational researcher, one a basic scientist with expertise in nonhuman primate models of HIV – piloted successfully in SIV+ pigtailed macaques. Our closed-chest MI model most closely mirrors contemporary human MIs and our SIV+ pigtailed macaque model most closely reproduces HIV-related immune responses. This will enable us to determine effects of HIV/SIV and ART on post-MI cardiac structure and function in Aim 1. In Aim 2, we will perform targeted depletions of CD4+ and CD8+ T cells to determine the role of these subsets in HIV/SIV-related response to MI. Finally, in Aim 3, we will administer targeted immunotherapies to block T cell activation/co-stimulation and inhibit peripheral monocyte recruitment and trafficking – immuno-modulatory interventions that may be particularly promising in quelling SIV/HIV-related immune activation and ameliorating post-MI damage. Our application is highly responsive to the National Heart, Lung, and Blood Institute (NHLBI)'s notice of special interest (NOSI) NOT-HL-19-677 for applications proposing exploratory and innovative research to understand HIV-associated cardiovascular diseases. We expect that our study will yield new insights into the immunopathogenesis MI and HF in HIV and inform future efforts to curb myocardial damage, dysfunction, and resulting HF for people with HIV.