Monday, December 11, 2023
12/11/2023
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
