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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：
10675714
负责人：
Moises Arturo Huaman Joo
金额：
$ 53.24万
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/10675714
关键词：
Acute myocardial infarction Address Affect Aftercare Angiography Antimycobacterial Agents Aorta Area Arterial Fatty Streak Atherosclerosis Biological Markers CD36 gene Calcium Cardiovascular Diseases Cells Clinic Coronary Coronary Arteriosclerosis Coronary artery Data Development Diameter Enrollment Epidemic Event Exhibits Flow Cytometry Future General Population Genus Mycobacterium HIV HIV Infections HIV/TB High Prevalence Immune In Vitro Individual Infection Control Inflammatory Interferon Type II 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 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 immune modulating agents infection rate metabolic profile monocyte mouse model multiplex assay 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.

项目总结