In the antiretroviral therapy (ART) era, HIV-infected persons remain at increased risk for cardiovascular disease(1-4) that we and others have linked to persistent inflammation(5-11). The precise mechanisms driving persistent inflammation are not known, but may include: low level HIV-1 replication(12), copathogens(13), microbial translocation(14), and pro-inflammatory lipids (e.g. oxidized LDL)(15);that can each activate innate defenses, inducing inflammatory cytokines, altering endothelial cell and immune cell function(8, 16). Mechanisms whereby these perturbations drive cardiovascular (CV) risk in ART treated HIV infection are also not well understood. We propose that a complex inflammatory interaction among monocytes, platelets, effector CD8+ T cells and the endothelium promotes the development of vascular disease and propose mechanistic studies to define this. We have found profound increases in expression of the procoagulant tissue factor (TF) on monocytes, their subsets(17, 18), platelets(19), and in plasma as circulating microparticles(9, 17, 20) in HIV disease and have found a superimposable monocyte phenotype in uninfected persons with acute coronary syndromes(18). We also find that expansion of effector CD8+ T cells is linked to cardiovascular morbidity in ART treated HIV infection(21, 22) and while CD8+ T cell infiltration has been linked to vascular inflammation in uninfected persons(23), mechanisms driving this are also not clear. We find that the expanded effector CD8+ T cells in HIV infection are enriched for expression of both CX3CR1 and protease activated receptor-1 (PAR-1) a receptor activated by thrombin. We hypothesize that inflammatory, procoagulant CX3CR1+ monocytes in HIV- infection drive vascular inflammation by promoting thrombosis, accumulation of foam cells and thrombin- mediated activation of PAR-1 on proximate CX3CR1+ CD8+ T cells and that these phenotypes are mediated in part by low levels of Kruppel-like factors (KLF)-2 and 4 in monocytes and endothelium.
Sp Aim 1 : To explore the role of oxidized lipids in driving monocyte activation, coagulation, and inflammation in ART-treated HIV-infection, and to define the molecular basis of these effects.
Sp Aim 2 : To more fully characterize the phenotype of the expanded CX3CR1+ PAR-1+ CD8+ T cells that are linked to CV disease risk in treated HIV-infection and to investigate the role of PAR-1 activation and the effects of LPS and oxLDL-activated monocytes on these cells.
Sp Aim 3 : To apply a novel flow based system to explore the effects of microbial products and oxidized lipids on immune cell trans-endothelial cell (EC) migration and to apply this to compare intercellular interactions and trans-endothelial migration patterns of monocytes and CD8+ T cells of ART-treated patients and healthy controls.
HIV-infected patients are at greater risk for cardiovascular events, including heart attacks, than are uninfected controls. The mechanism(s) behind this increased risk are poorly understood, but may include chronic inflammation, altered lipid profiles, and immune activation, and designing experiments to elucidate them, may provide targets for therapeutic intervention.
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