Abstract 100: HIV Protein Tat Induces Macrophage Dysfunction and Atherosclerosis Development in LDLR-deficient Mice
Introduction: As the average lifespan of HIV-infected patients receiving anti-retroviral therapy lengthens, morbidity and mortality from cardiovascular disease pose considerable challenges. HIV infection is consistently associated with increased risk of atherosclerosis development, but the underlying mechanisms remain elusive. HIV-1 Tat protein, a transcriptional activator of HIV virus, has been shown to activate NF-κB signaling and promote inflammation in vitro. However, the atherogenic effects of HIV-1 Tat have not been investigated in vivo. Macrophage is one of the major cell types involved in the initiation and progression of atherosclerosis. We and others have previously demonstrated that NF-κB signaling functions in macrophages to regulate atherogenesis. This study aims to investigate the impact of HIV-1 Tat exposure on macrophage functions and atherogenesis. Hypothesis: HIV-1 Tat activates IκB kinase β (IKKβ), a central coordinator in inflammation through activation of NF-κB, to induce macrophage dysfunction and atherosclerosis development. Methods: To investigate the effects of HIV-1 Tat on macrophage IKKβ signaling and atherosclerosis development in vivo, myeloid-specific IKKβ-deficient LDLR-deficient (IKKβ ΔMye LDLR -/- ) mice and their control littermates (IKKβ F/F LDLR -/- ) were exposed to recombinant HIV-1 Tat for 12 weeks. The effects of HIV-1 Tat on macrophage functions including inflammatory responses, adhesion and migration properties were also studied. Results and Conclusions: HIV-1 Tat significantly increased atherosclerotic lesion size in aortic root and brachiocephalic artery of IKKβ F/F LDLR -/- but not IKKβ ΔMye LDLR -/- mice. Deficiency of myeloid IKKβ attenuated macrophage inflammatory responses and decreased atherosclerotic lesional inflammation in IKKβ ΔMye LDLR -/- mice. In addition, HIV-1 Tat stimulated adhesion and migration properties of control macrophages but had no effects on IKKβ-deficient macrophages. In conclusion, our findings reveal the atherogenic effects of HIV-1 Tat in vivo and demonstrate a pivot role of myeloid IKKβ in HIV-1 Tat-driven atherogenesis.