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.

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