Coronary Atherosclerosis and Immune Activation in HIV and Tuberculosis Infection

HIV 和结核感染中的冠状动脉粥样硬化和免疫激活

基本信息

批准号：
10481301
负责人：
Moises Arturo Huaman Joo
金额：
$ 54.5万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-02 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10481301
关键词：
Acute myocardial infarction Address Affect Aftercare Angiography Area Arterial Fatty Streak Atherosclerosis Biological Markers CD36 gene Calcium Caliber Cardiovascular Diseases Cells Clinic Coronary Coronary Arteriosclerosis Coronary artery Data Development Enrollment Epidemic Event Exhibits Flow Cytometry Future GTP-Binding Protein alpha Subunits, Gs General Population Genus Mycobacterium HIV HIV Infections HIV/TB High Prevalence Immune Immunomodulators In Vitro Individual Infection Control Inflammatory Interferons Interleukin-6 Intervention Intervention Trial Knowledge Link Modeling Mus Mycobacterium Infections Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Participant Pathogenesis Peripheral Blood Mononuclear Cell Persons Peru Phenotype Plasma Population Prevalence Production Recording of previous events Research Risk Risk Factors Role Stenosis Stimulus T-Cell Activation T-Lymphocyte TNF gene Testing Therapeutic Time Tobacco use Tuberculosis Variant Visit age group aged antiretroviral therapy atherosclerosis risk base cardiometabolism cardiovascular disorder risk clinically relevant co-infection cohort coronary computed tomography angiography coronary plaque cytokine density design experimental study high dimensionality high risk high risk population immune activation metabolic profile monocyte mouse model multiplex assay mycobacterial novel marker oxidized low density lipoprotein prevent recruit scavenger receptor screening sex tomography uptake

项目摘要

Project Summary Persons living with HIV (PLWH) have a 1.5- to 2-fold increased risk of cardiovascular disease (CVD) compared to the general population. Immune activation, particularly driven by coinfections, is considered an important contributor in that enhanced risk. However, whether Mycobacterium tuberculosis (Mtb) coinfection increases CVD risk in PLWH is unknown. Latent tuberculosis infection (LTBI) affects a quarter of the world population, with coinfection rates as high as 50% in HIV-endemic areas. Our preliminary data point towards an important role of LTBI in augmenting CVD risk. In HIV-uninfected individuals, we have demonstrated that LTBI is associated with increased likelihood of acute myocardial infarction and higher prevalence of obstructive coronary artery disease, independent of traditional CVD risk factors. In proof-of-concept mouse experiments, we revealed that persistent, asymptomatic mycobacterial infection exacerbated aortic plaque development, and that plaque burden directly correlated with alterations of monocyte populations. Our overall hypothesis is that in PLWH, LTBI coinfection contributes to the development of atherosclerotic CVD (ASCVD) through enhanced immune activation and pro-inflammatory stimuli resulting in increased plaque burden and instability. In this project, we will study PLWH with and without LTBI in Lima, Peru, a TB-endemic area. In Aim 1 of this proposal, we will define the burden of obstructive coronary artery disease and plaque vulnerability in PLWH with LTBI using advanced coronary computed tomography angiography studies. In Aim 2, we will determine how LTBI and LTBI treatment affects the activation, function, and metabolic profile of monocytes and Mtb- specific T cells in PLWH, using high-dimensional multi-parameter spectral flow cytometry for in-depth longitudinal immune cell profiling. Finally, we will study the relationship between variations on immune activation markers and changes on coronary plaque volume over 2 years. Successful accomplishment of the proposed research aims will define the role of LTBI as a contributor of ASCVD risk and immune activation in PLWH. Our results will set the stage for targeted mechanistic studies and interventional trials aimed at safely reducing underlying immune activation in PLWH with LTBI, and emphasize the importance of LTBI control as a therapeutic strategy to mitigate ASCVD risk. Moreover, the knowledge gained will further enhance our broader mechanistic understanding of ASCVD.

项目概要与其他人相比，艾滋病毒感染者 (PLWH) 患心血管疾病 (CVD) 的风险增加 1.5 至 2 倍给广大民众。免疫激活，特别是由合并感染驱动的免疫激活，被认为是一个重要的因素风险增加的贡献者。然而，结核分枝杆菌 (Mtb) 合并感染是否会增加 PLWH 的 CVD 风险尚不清楚。潜伏性结核感染（LTBI）影响着世界四分之一的人口，在艾滋病毒流行地区，合并感染率高达50%。我们的初步数据表明一个重要的 LTBI 在增加 CVD 风险中的作用。在未感染 HIV 的个体中，我们已经证明 LTBI 是与急性心肌梗塞的可能性增加和梗阻的患病率较高有关冠状动脉疾病，独立于传统的CVD危险因素。在概念验证小鼠实验中，我们发现持续的、无症状的分枝杆菌感染加剧了主动脉斑块的形成，并且斑块负荷与单核细胞群的变化直接相关。我们的总体假设是在 PLWH 中，LTBI 合并感染通过以下方式促进动脉粥样硬化 CVD (ASCVD) 的发展：增强的免疫激活和促炎刺激导致斑块负担增加和不稳定。在这个项目中，我们将研究结核病流行区秘鲁利马有和没有 LTBI 的感染者。在这个目标1中提案中，我们将定义 PLWH 中阻塞性冠状动脉疾病的负担和斑块易损性使用先进的冠状动脉计算机断层扫描与 LTBI 血管造影研究。在目标 2 中，我们将确定 LTBI 和 LTBI 治疗如何影响单核细胞和 Mtb 的激活、功能和代谢特征 PLWH中的特异性T细胞，利用高维多参数光谱流式细胞术进行深入研究纵向免疫细胞分析。最后，我们将研究免疫变异之间的关系激活标记物和 2 年来冠状动脉斑块体积的变化。圆满完成了拟议的研究目标将确定 LTBI 作为 ASCVD 风险和免疫激活的贡献者的作用艾滋病病毒感染者。我们的结果将为有针对性的机制研究和旨在安全地进行干预的试验奠定基础减少 LTBI 感染者潜在的免疫激活，并强调 LTBI 控制作为降低 ASCVD 风险的治疗策略。此外，所获得的知识将进一步增强我们更广泛的知识 ASCVD 的机制理解。