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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56HL126563-01
Application #
8915901
Study Section
Special Emphasis Panel (ZHL1-CSR-B (S1))
Program Officer
Fleg, Jerome
Project Start
2014-09-11
Project End
2015-08-31
Budget Start
2014-09-11
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$810,099
Indirect Cost
$139,793
Name
Ohio State University
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Kulkarni, Manjusha M; Ratcliff, Annette N; Bhat, Menakshi et al. (2017) Cellular fatty acid synthase is required for late stages of HIV-1 replication. Retrovirology 14:45
Belury, Martha A; Bowman, Emily; Gabriel, Janelle et al. (2017) Prospective Analysis of Lipid Composition Changes with Antiretroviral Therapy and Immune Activation in Persons Living with HIV. Pathog Immun 2:376-403
Funderburg, Nicholas T; Xu, Dihua; Playford, Martin P et al. (2017) Treatment of HIV infection with a raltegravir-based regimen increases LDL levels, but improves HDL cholesterol efflux capacity. Antivir Ther 22:71-75
Shive, Carey L; Clagett, Brian; McCausland, Marie R et al. (2016) Inflammation Perturbs the IL-7 Axis, Promoting Senescence and Exhaustion that Broadly Characterize Immune Failure in Treated HIV Infection. J Acquir Immune Defic Syndr 71:483-92
Funderburg, Nicholas T; Mehta, Nehal N (2016) Lipid Abnormalities and Inflammation in HIV Inflection. Curr HIV/AIDS Rep 13:218-25
Mudd, Joseph C; Panigrahi, Soumya; Kyi, Benjamin et al. (2016) Inflammatory Function of CX3CR1+ CD8+ T Cells in Treated HIV Infection Is Modulated by Platelet Interactions. J Infect Dis 214:1808-1816
Panigrahi, Soumya; Freeman, Michael L; Funderburg, Nicholas T et al. (2016) SIV/SHIV Infection Triggers Vascular Inflammation, Diminished Expression of Kr├╝ppel-like Factor 2 and Endothelial Dysfunction. J Infect Dis 213:1419-27
Turner, Abigail Norris; Maierhofer, Courtney; Funderburg, Nicholas T et al. (2016) High levels of self-reported prescription opioid use by HIV-positive individuals. AIDS Care 28:1559-1565
Hileman, Corrilynn O; Turner, Randi; Funderburg, Nicholas T et al. (2016) Changes in oxidized lipids drive the improvement in monocyte activation and vascular disease after statin therapy in HIV. AIDS 30:65-73
Zidar, David A; Juchnowski, Steven; Ferrari, Brian et al. (2015) Oxidized LDL Levels Are Increased in HIV Infection and May Drive Monocyte Activation. J Acquir Immune Defic Syndr 69:154-60

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