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

心肌对缺血引起的功能障碍和心力衰竭的脆弱性：HIV/SIV、ART 和靶向免疫治疗的影响

• 批准号: 10426282
• 负责人: Matthew Joel Feinstein
• 金额: $ 78.28万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426282
• 关键词: Address; Affect; Anatomy; Animal Model; Animals; Area; Autopsy; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cells; Chemotactic Factors; Chest; Chronic; Cicatrix; Clinical; Collaborations; Congestive; Coronary; Data; Equilibrium; Event; Fibrosis; Functional disorder; Future; General Population; Genes; HIV; HIV antiretroviral; Heart; Heart Diseases; Heart failure; Histology; Human; Image; Immune; Immune Targeting; Immune response; Immunotherapy; Impairment; Inflammation; Inflammatory; Injury; Interdisciplinary Study; Intervention; Investigation; Ischemia; Lead; Lesion; Lymphoid Cell; Macaca; Macaca nemestrina; Modeling; Mononuclear; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; National Heart, Lung, and Blood Institute; Observational Study; Organ; Pathogenesis; Pathogenicity; Pattern; Peripheral; Persons; Phenotype; Play; Predisposing Factor; RNA Interference; Recovery; Research; Research Personnel; Resolution; Risk; Risk Factors; Role; SIV; Scientist; Smoking; Stress; Structure; T-Cell Activation; T-Lymphocyte; Time; Tissues; Viral; Virus; antagonist; antiretroviral therapy; base; cardiac magnetic resonance imaging; cardiovascular disorder risk; cardiovascular risk factor; career; clinically relevant; comorbidity; coronary fibrosis; heart damage; heart function; high risk; immune activation; immunomodulatory therapies; immunoregulation; innovation; insight; interest; macrophage; monocyte; mortality; multidisciplinary; myocardial damage; nonhuman primate; novel; peripheral blood; prevent; recruit; response; simian human immunodeficiency virus; tissue stress; trafficking; translational scientist

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.

概括 人类免疫缺陷病毒 (HIV) 感染者患心肌梗塞 (MI) 的风险高出 1.25 至 2 倍 与未感染 HIV 的人相比，冠状动脉缺血和心力衰竭 (HF) 是 HF 的最常见原因。 总体而言，这可能是 HIV 感染者 (PWH) 近期发生心力衰竭的特别重要原因； 证明在抗逆转录病毒治疗（ART）下进行病毒控制的感染者的心肌面积是其两倍 与具有相似危险因素和冠状动脉解剖结构的未感染 HIV 的人相比，MI 后的（心肌）损伤更大。 这些发现的潜在原因与持续的免疫失调和靶向不当有关 抗逆转录病毒治疗中慢性艾滋病毒的特征是炎症，这可能使艾滋病毒感染者特别容易发病。 缺血期间心肌梗死的传播，以及心肌梗死期间和之后的心肌损伤和由此导致的心力衰竭。 慢性免疫激活和炎症与 PWH 的哮喘心血管风险相关，并且 这些关联对于感染者来说比未感染者更强。但是，尚不清楚与艾滋病毒的相关性如何。 免疫激活异常会影响心脏损伤、功能障碍，并最终导致心力衰竭 冠状动脉缺血和心肌梗死仅靠观察性研究无法回答这个问题。 因此，需要模型来 (1) 确定 HIV、ART 和相关免疫失调可能如何影响 缺血性心脏重塑和由此引起的心力衰竭，以及 (2) 确定改善的免疫调节疗法 缺血性心脏损伤、功能障碍和心力衰竭在 HIV 中的作用。 HIV/猿猴免疫缺陷病毒 (SIV)、ART 以及特定淋巴细胞亚群和趋化性 我们将使用一种新的缺血再灌注心肌梗死模型。 联合PI——一名是心脏病专家和临床/转化研究员，一名是具有以下专业知识的基础科学家 非人类灵长类 HIV 模型 – 在 SIV+ 猪尾猕猴中成功试验 我们的闭胸 MI。 模型最接近当代人类 MI，而我们的 SIV+ 辫子猕猴模型最接近 重现 HIV 相关的免疫反应，这将使我们能够确定 HIV/SIV 和 ART 对艾滋病毒/SIV 的影响。 目标 1 中的 MI 后心脏结构和功能。在目标 2 中，我们将进行 CD4+ 和 CD4+ 的定向耗竭 CD8+ T 细胞确定这些亚群在 HIV/SIV 相关 MI 反应中的作用。 进行靶向免疫疗法以阻断 T 细胞激活/共刺激并抑制外周单核细胞 招募和贩运——免疫调节干预措施在平息疫情方面可能特别有希望 SIV/HIV 相关的免疫激活和改善 MI 后损伤我们的应用程序对 SIV/HIV 相关的免疫激活和改善 MI 后损伤具有高度响应性。 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的申请，以了解艾滋病毒相关的心血管疾病 我们期望我们的研究能够对 HIV 和 HF 的免疫发病机制产生新的见解。 为未来遏制艾滋病毒感染者心肌损伤、功能障碍以及由此导致的心力衰竭的努力提供信息。