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 与艾滋病毒（PLWH）患者相比，患有艾滋病毒（PLWH）的人患心血管疾病（CVD）的风险增加了1.5至2倍 向普通人群。免疫激活，尤其是由共感染驱动的，被认为是重要的 这种增强风险的贡献者。但是，分枝杆菌结核病（MTB）共感染是否增加 PLWH中的CVD风险尚不清楚。潜在的结核病感染（LTBI）影响了世界四分之一的人口， HIV流行区域的共感染率高达50％。我们的初步数据指向一个重要的 LTBI在增加CVD风险中的作用。在艾滋病毒未感染的个体中，我们已经证明了LTBI是 与急性心肌梗塞的可能性增加和阻塞性较高的患病率有关 冠状动脉疾病，与传统CVD风险因素无关。在概念验证的鼠标实验中， 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育， 斑块负担与单核细胞种群的改变直接相关。我们的总体假设是 在PLWH中，LTBI共感染有助于通过 增强的免疫激活和促炎性刺激，导致牙菌斑负担增加和不稳定。 在这个项目中，我们将在秘鲁的利马（TB-Dememic地区）研究PLWH，并没有LTBI。在目标1中 提案，我们将定义PLWH中阻塞性冠状动脉疾病和斑块脆弱性的负担 使用高级冠状动脉断层扫描血管造影研究的LTBI。在AIM 2中，我们将确定 LTBI和LTBI处理如何影响单核细胞和MTB-的激活，功能和代谢谱 PLWH中的特定T细胞，使用高维多参数光流式细胞仪进行深入 纵向免疫细胞分析。最后，我们将研究免疫变化之间的关系 激活标记和2年内冠状动脉斑块体积的变化。成功完成 拟议的研究目的将定义LTBI作为ASCVD风险和免疫激活的作用 plwh。我们的结果将为有针对性的机械研究和旨在安全的介入试验奠定阶段 用LTBI降低PLWH中的潜在免疫激活，并强调LTBI控制的重要性 减轻ASCVD风险的治疗策略。此外，获得的知识将进一步增强我们的广泛 对ASCVD的机械理解。