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

摘要 携带人类免疫缺陷病毒(HIV)的人患心肌梗死(MI)的风险要高1.25到2倍 和心力衰竭(HF)的人比没有艾滋病毒的人。冠脉缺血和心肌梗死是心力衰竭最常见的原因 一般来说，这可能是导致艾滋病毒携带者(PWH)发生心力衰竭的特别重要原因；我们最近 在抗逆转录病毒治疗(ART)中，病毒控制的PWH有两倍于心肌的范围 心肌梗死后的(心肌)损害比没有艾滋病毒的人更多，他们有相似的危险因素和冠状动脉解剖。一个 这些发现的潜在原因与持续性免疫失调和靶向不当有关 ART上慢性HIV的特征是炎症。这些都可能使pwh特别容易发病。 缺血时心肌梗死的传播，以及心肌梗死期间和心肌梗死后的心肌损害和导致的心衰。 慢性免疫激活和炎症与PWH心血管风险增加相关，以及 对于PWH来说，这些关联比未感染的人更强。然而，目前尚不清楚艾滋病毒与 免疫激活异常会影响心脏损害、功能障碍，最终导致心衰。 冠脉缺血和心肌梗死。单靠观察性研究无法回答这个问题。信息量大的动物 因此，需要模型来(1)确定艾滋病毒、抗逆转录病毒治疗和相关的免疫失调如何影响 缺血性心脏重构和由此导致的心衰，以及(2)确定可改善的免疫调节疗法 HIV患者的缺血性心脏损害、功能障碍和心力衰竭。在本应用程序中，我们建议确定 艾滋病毒/猴免疫缺陷病毒(SIV)、ART以及特定的淋巴细胞亚群和趋化作用 心肌梗死后不利心脏重塑的因素。我们将使用一种新的缺血再灌注心肌梗死模型 合作-PIs-一个是心脏病专家和临床/翻译研究人员，一个是具有以下专业知识的基础科学家 非人灵长类艾滋病毒模型在SIV+辫尾猕猴中成功试行。我们的闭胸式心肌梗死 模型最接近反映当代人类MI和我们的SIV+辫子猕猴模型最接近 复制与艾滋病毒相关的免疫反应。这将使我们能够确定艾滋病毒/SIV和抗逆转录病毒治疗对 心肌梗死后的心脏结构和功能在目标1。在目标2，我们将进行有针对性的消耗CD4+和 CD8+T细胞来确定这些亚群在HIV/SIV相关心肌梗死应答中的作用。最后，在目标3中，我们将 实施靶向免疫治疗以阻断T细胞激活/共刺激并抑制外周血单核细胞 招募和贩运--可能特别有希望平息的免疫调节干预 SIV/HIV相关免疫激活和改善心肌梗死后损害。我们的应用程序高度响应 国家心肺血液研究所S特别关注(NOSI)NOT-HL-19-677 提出探索性和创新性研究以了解艾滋病毒相关心血管疾病的应用 疾病。我们预计，我们的研究将对艾滋病毒和艾滋病的免疫发病机制MI和HF产生新的见解。 为未来遏制艾滋病毒携带者心肌损伤、功能障碍和由此导致的心衰的努力提供信息。

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.