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

• 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
• 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

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.

项目摘要 艾滋病毒感染者（PLWH）患心血管疾病（CVD）的风险比普通人高1.5至2倍。 对大众来说。免疫激活，特别是由合并感染驱动，被认为是一个重要的 这一风险的增加。然而，结核分枝杆菌（Mtb）合并感染是否增加 PLWH中的CVD风险未知。潜伏性结核感染（LTBI）影响着世界人口的四分之一， 在艾滋病流行地区，合并感染率高达50%。我们的初步数据显示， 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 与急性心肌梗死的可能性增加和阻塞性心肌梗死的患病率增加相关。 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， 我们揭示了持续的、无症状的分枝杆菌感染加剧了主动脉斑块的发展， 并且斑块负荷与单核细胞群的改变直接相关。我们的总体假设是 在PLWH中，LTBI合并感染通过以下途径促进动脉粥样硬化性CVD（ASCVD）的发展： 增强的免疫激活和促炎刺激导致斑块负荷和不稳定性增加。 在这个项目中，我们将在结核病流行区秘鲁的利马研究PLWH伴和不伴LTBI的情况。目标1 我们将定义PLWH中阻塞性冠状动脉疾病和斑块易损性的负担 使用先进的冠状动脉计算机断层扫描血管造影研究与LTBI。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的活化、功能和代谢特征- PLWH中特异性T细胞，使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，我们将研究免疫功能变化之间的关系。 激活标志物和2年内冠状动脉斑块体积的变化。成功完成 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， PLWH。我们的研究结果将为有针对性的机制研究和干预性试验奠定基础， 减少潜在的免疫激活PLWH与LTBI，并强调LTBI控制的重要性， 降低ASCVD风险的治疗策略。此外，所获得的知识将进一步提高我们更广泛的 对ASCVD的机械理解。