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Principal Investigator: Moises Arturo Huaman Joo
Organization: UNIVERSITY OF CINCINNATI
Fiscal Year: 2024
Award: $607,624
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <(TNF)-α><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute myocardial infarct><Acute myocardial infarction><Address><Affect><After Care><After-Treatment><Aftercare><Angiogram><Angiography><Anti Mycobacterial Agents><Antimycobacterial Agents><Aorta><Area><Arterial Fatty Streak><Arterial Fatty Streaks><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Biological Markers><Blood Plasma><Blood monocyte><CD36><CD36 gene><Cachectin><Calcium><Cardiac artery><Cardiovascular Diseases><Cell Body><Cells><Clinic><Coronary><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Coronary CT Angiography><Coronary artery><Data><Development><Diameter><Enrollment><Epidemic><Event><Exhibits><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Future><GP3B><GP4><GPIV><General Population><General Public><Genus Mycobacterium><HIV><HIV Infections><HIV/Mtb><HIV/TB><HIV/mycobacterium tuberculosis><HIV/tuberculosis><HPGF><HTLV-III Infections><HTLV-III-LAV Infections><Heart artery><Hepatocyte-Stimulating Factor><High Prevalence><History><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Hybridoma Growth Factor><IFN-Gamma><IFN-beta 2><IFN-g><IFN-γ><IFNB2><IFNG><IFNγ><IL-6><IL6 Protein><IMiD><Immune><Immune Cell Activation><Immune Interferon><Immune modulatory therapeutic><Immunes><In Vitro><Individual><Infection Control><Inflammatory><Interferon Gamma><Interferon Type II><Interleukin-6><Intervention><Intervention Strategies><Intervention Trial><Interventional trial><Knowledge><LAV-HTLV-III><Link><Lymphadenopathy-Associated Virus><M tb><M tuberculosis><M tuberculosis antigen><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis antigen><M. tuberculosis infection><M. tuberculosis/HIV><M.tb antigen><M.tb infection><M.tuberculosis infection><MGI-2><MTB infection><Macrophage-Derived TNF><Marrow monocyte><Mice><Mice Mammals><Modeling><Monocyte-Derived TNF><Mtb antigen><Murine><Mus><Mycobacterial Infection><Mycobacterium><Mycobacterium Infections><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis antigens><Mycobacterium tuberculosis infection><Myeloid Differentiation-Inducing Protein><OxLDL><PBMC><Participant><Pathogenesis><Pathologic Constriction><Pathological Constriction><Peripheral Blood Mononuclear Cell><Persons><Peru><Phenotype><Plasma><Plasma Serum><Plasmacytoma Growth Factor><Population><Prevalence><Production><Recording of previous events><Research><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Role><SCARB3><Stenosis><Stimulus><T-Cell Activation><T-Cells><T-Lymphocyte><TB infection><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Time><Tobacco Consumption><Tobacco use><Tuberculosis><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Variant><Variation><Virus-HIV><Visit><acetyl-LDL receptor><acetylated LDL receptor><activate T cells><age group><aged><angiographic imaging><antimycobacterial><antiretroviral therapy><antiretroviral treatment><atheromatosis><atherosclerosis plaque><atherosclerosis risk><atherosclerotic coronary disease><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic risk><atherosclerotic vascular disease><bio-markers><biologic marker><biomarker><cardiometabolic><cardiometabolism><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><clinical relevance><clinically relevant><co-infection><cohort><coinfection><computed coronary angiography scanning><coronary CTA><coronary arterial disease><coronary computed tomography angiography><coronary plaque><cytokine><density><design><designing><developmental><disseminated TB><disseminated tuberculosis><enroll><experiment><experimental research><experimental study><experiments><flow cytophotometry><high dimensionality><high risk><high risk group><high risk individual><high risk people><high risk population><histories><immune activation><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulatory agents><immune modulatory drugs><immunomodulating agents><immunomodulating drugs><immunomodulator agent><immunomodulator drug><immunomodulator medication><immunomodulator prodrug><immunomodulator therapeutic><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><infection due to Mycobacterium tuberculosis><infection rate><interferon beta 2><interventional strategy><lFN-Gamma><metabolic profile><monocyte><mouse model><mtb><multiplex assay><murine model><new marker><novel biomarker><novel marker><ox-LDL><oxidized LDL><oxidized low density lipoprotein><post treatment><prevent><preventing><rate of infection><recruit><scavenger receptor><screening><screenings><sex><social role><thymus derived lymphocyte><tobacco product use><tomography><tuberculosis infection><tuberculous spondyloarthropathy><uptake><vulnerable plaque>