In the antiretroviral therapy (ART) era, HIV-infected persons remain at increased risk for cardiovascular disease1-4 that we5-7 and others have linked to persistent inflammation8-13. The precise mechanisms driving persistent inflammation are not known, but may include: low level HIV-1 replication14, copathogens15, microbial translocation16, and pro-inflammatory lipids (e.g. oxidized LDL)17, that can each activate innate defenses, inducing inflammatory cytokines, and altering endothelial cell and immune cell function11,18. Mechanisms whereby these perturbations drive cardiovascular risk in ART treated HIV-infection are also not well understood. We propose that a complex inflammatory interaction among monocytes, 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 subsets19,20, platelets21, and in plasma as circulating microparticles12,19,22 in HIV disease. Proportional representation of CD16+ monocyte subsets are increased in HIV infection20; these cells are enriched for CX3CR1(fractalkine receptor) expression, and monocytes from HIV+ patients have increased expression of the integrin LFA-1, promoting vascular homing and adhesion. We also find that expansion of effector CD8+ T cells is linked to cardiovascular (CV) morbidity in ART treated HIV-infection23,24; and while CD8+ T cell infiltration has been linked to vascular inflammation in uninfected persons25, 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 that can be cleaved by thrombin and is then activated. We hypothesize that inflammatory, procoagulant CX3CR1+ monocytes in HIV- infection drive vascular inflammation by promoting thrombosis, maturing into foam cells, driving thrombin- mediated activation of PAR-1 on proximate CX3CR1+ CD8+ T cells that also patrol the fractalkine+ endothelium and that these activated phenotypes are sustained in part, by low levels of Krppel-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 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; designing experiments to elucidate these mechanisms may provide targets for therapeutic intervention.
| 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 |
| Hileman, Corrilynn O; Funderburg, Nicholas T (2017) Inflammation, Immune Activation, and Antiretroviral Therapy in HIV. Curr HIV/AIDS Rep 14:93-100 |
| Kulkarni, Manjusha; Bowman, Emily; Gabriel, Janelle et al. (2016) Altered Monocyte and Endothelial Cell Adhesion Molecule Expression Is Linked to Vascular Inflammation in Human Immunodeficiency Virus Infection. Open Forum Infect Dis 3:ofw224 |
