Baseline markers of inflammation and coagulation have been shown to be powerful predictors of adverse outcomes in patients with HIV infection. In a study of 5098 participants in a completed randomized, controlled trial there were 252 patients with a primary cardiovascular event over a median follow-up of 29 months. The risk of such an event was highest in those patients with the highest levels of IL-6, hsCRP and D-dimer. Disruption of vascular integrity by trauma and other tissue insults leads to inflammation and activation of the coagulation cascade. The serine protease thrombin links these 2 processes. The proinflammatory function of thrombin is mediated by activation of protease-activated receptor 1 (PAR-1). We found that peripheral blood effector memory CD4(+) and CD8(+) T lymphocytes expressed PAR-1 and that expression was increased in CD8(+) T cells from human immunodeficiency virus (HIV)-infected patients. Thrombin enhanced cytokine secretion in CD8(+) T cells from healthy controls and HIV-infected patients. In addition, thrombin induced chemokinesis, but not chemotaxis, of CD8(+) T cells, which led to structural changes, including cell polarization and formation of a structure rich in F-actin and phosphorylated ezrin-radexin-moesin proteins. These findings suggest that thrombin mediates cross-talk between the coagulation system and the adaptive immune system at sites of vascular injury through increased T-cell motility and production of proinflammatory cytokines. The susceptibility of macrophages to HIV-1 infection is modulated during monocyte differentiation. IL-27 is an anti-HIV cytokine that also modulates monocyte activation. IL-27 was found to promote monocyte differentiation into macrophages that are nonpermissive for HIV-1 infection. Although IL-27 treatment did not affect expression of macrophage differentiation markers or macrophage biological functions, it confered HIV resistance by down-regulating spectrin βnonerythrocyte 1 (SPTBN1), a required host factor for HIV-1 infection as well as inducing the expression of novel microRNAS.

Project Start
Project End
Budget Start
Budget End
Support Year
24
Fiscal Year
2013
Total Cost
$1,402,715
Indirect Cost
City
State
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Zip Code
Sowrirajan, Bharatwaj; Saito, Yoshiro; Poudyal, Deepak et al. (2017) Interleukin-27 Enhances the Potential of Reactive Oxygen Species Generation from Monocyte-derived Macrophages and Dendritic cells by Induction of p47(phox). Sci Rep 7:43441
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