Antiretroviral drugs and tobacco smoke dysregulate human platelets: A novel investigation into the etiology of HIV co-morbid cardiovascular disease.

Abstract

Abstract While antiretroviral drugs (ARVs) successfully suppress Human Immunodeficiency Virus (HIV), HIV-infected persons still have a shorter lifespan and are at higher risk of developing cardiovascular disease (CVD) compared to uninfected persons. CVD is the number one cause of death globally, and is now appreciated as an inflammatory disease. HIV-infected persons experience chronic inflammation, thought to be caused by low levels of HIV proteins, daily use of ARVs, and increased rates of smoking. The impact of ARVs on CVD risk remains unclear, with some studies linking ARVs to CVD. Additionally, when controlled for smoking status HIV-infected persons were still at greater risk for CVD. Platelets are important in the development of CVD, but the effects of ARVs on platelets are unstudied. Additionally, cigarette smoke is known to activate platelets, inducing inflammation. Our novel study investigates the effects of ARVs and cigarette smoke, alone and in combination, on human platelet function. Our striking in vitro findings demonstrate that the ARVs Ritonavir and Darunavir, as well as cigarette smoke, dysregulate platelet function. Treatment with the protease inhibitor Ritonavir resulted in a dose-dependent increase in platelet production of proinflammatory mediator prostaglandin E2 (PGE2) (p<0.001). Additionally, when combined with cigarette smoke, Darunavir induced production of PGE2 (p<0.01). Combined doses of Ritonavir and Darunavir at physiological concentrations inhibited platelet spreading, similar to the effect of cigarette smoke. We hypothesize that cigarette smoke and ARVs act in combination to activate platelets and thus contribute to the chronic inflammation which leads to CVD.