The proinflammatory functions of granzymes and their impact on endothelial inflammation/injury

Project Summary While antiretroviral therapy successfully suppresses HIV replication, immune activation and inflammation persist, albeit at lower levels, and has been associated to as an important contributor of morbidity and mortality in PWH. The clinical significance of immune activation is the evidence that demonstrates that HIV- associated T cell immune activation and inflammation drive cardiovascular risk, independent of the traditional risk factors, duration of antiretroviral treatment, and CD4 counts. Persistent HIV reservoirs are independently associated with incident carotid plaque, and people with coronary artery atherosclerotic plaques show higher levels of HIV DNA compared to those without disease. The molecular pathways by which HIV contributes to the increased risk is largely unknown, and difficult the development of more targeted therapies. CD8 T cell immune activation is associated with endothelial inflammation and dysfunction, and in this study, we hypothesize that HIV-driven CD8 T cell immune activation promotes secretion of granzymes contributing to vascular inflammation/injury. We will test this hypothesis by: Aim1. Granzymes expression regulation by memory CD8 T cell subsets and virus-specific CD8 T cells recruited to the sites of vascular injury to define their proinflammatory vs cytotoxic potential. Aim2. Granzyme expressing CD8 T cells enhance atherosclerosis progression during infection. We will assess the extracellular contribution of granzymes and their impact in the progression of a disease during infection.