Inflammatory Function of CX3CR1+ CD8+ T Cells in Treated HIV Infection Is Modulated by Platelet Interactions.

Increases in inflammation, coagulation, and CD8+ T-cell numbers are associated with an elevated cardiovascular disease (CVD) risk in human immunodeficiency virus (HIV)-infected antiretroviral therapy (ART) recipients. Circulating memory CD8+ T cells that express the vascular endothelium-homing receptor CX3CR1 (fractalkine receptor) are enriched in HIV-infected ART recipients. Thrombin-activated receptor (PAR-1) expression is increased in HIV-infected ART recipients and is particularly elevated on CX3CR1+ CD8+ T cells, suggesting that these cells could interact with coagulation elements. Indeed, thrombin directly enhanced T-cell receptor-mediated interferon γ production by purified CD8+ T cells but was attenuated by thrombin-induced release of transforming growth factor ß by platelets. We have therefore identified a population of circulating memory CD8+ T cells in HIV infection that may home to endothelium, can be activated by clot-forming elements, and are susceptible to platelet-mediated regulation. Complex interactions between inflammatory elements and coagulation at endothelial surfaces may play an important role in CVD risk in HIV-infected ART recipients.

Inflammatory cytokines drive CD4+ T-cell cycling and impaired responsiveness to interleukin 7: implications for immune failure in HIV disease.

BACKGROUND: Systemic inflammation has been linked to a failure to normalize CD4(+) T-cell numbers in treated human immunodeficiency virus (HIV) infection. Although inflammatory cytokines such as interleukin 6 (IL-6) are predictors of disease progression in treated HIV infection, it is not clear how or whether inflammatory mediators contribute to immune restoration failure. METHODS: We examined the in vitro effects of IL-6 and interleukin 1ß (IL-1ß) on peripheral blood T-cell cycling and CD127 surface expression. RESULTS: The proinflammatory cytokine IL-1ß induces cell cycling and turnover of memory CD4(+) T cells, and IL-6 can induce low-level cycling of naive T cells. Both IL-1ß and IL-6 can decrease T-cell surface expression and RNA levels of CD127, the interleukin 7 receptor α chain (IL-7Rα). Preexposure of healthy peripheral blood mononuclear cells (PBMCs) to IL-6 or IL-1ß attenuates IL-7-induced Stat5 phosphorylation and induction of the prosurvival factor Bcl-2 and the gut homing integrin α4ß7. We found elevated expression of IL-1ß in the lymphoid tissues of patients with HIV infection that did not normalize with antiretroviral therapy. CONCLUSIONS: Induction of CD4(+) T-cell turnover and diminished T-cell responsiveness to IL-7 by IL-1ß and IL-6 exposure may contribute to the lack of CD4(+) T-cell reconstitution in treated HIV-infected subjects.