Highly active antiretroviral therapy (HAART) has significantly increased the life expectancy of HIV/AIDS patients. A serious side-effect is that HAART is associated with non-resolving inflammation and an increased risk for cardiovascular disease (CVD). Tobacco smoking also promotes CVD risk and is a major health issue for all individuals. It is of even greater concern in the HIV/AIDS population that is three times more likely to smoke (up to 70% smoke and they smoke intensely) compared to the general population (20% smoke). Platelets play a seminal role in cardiovascular-associated inflammation and thrombosis, and contribute to the etiology and pathogenesis of CVD. Tobacco smoke activates platelets. A major knowledge gap is that the combined effects of HAART and tobacco smoke on platelet activation and CVD risk are unknown. Our hypothesis is that HAART increases platelet dysregulation and HAART combined with tobacco smoke further promotes platelet dysregulation. The long term hypothesis and importance of this research proposal is that tobacco smoke places HIV-infected individuals undergoing HAART at even greater risk for developing comorbidities and mortality from platelet activation that causes CVD. Our goal is to perform essential basic in vitro human platelet function studies to determine the impact and mechanisms underlying the combined effects of tobacco smoke and key antiretroviral therapies on platelet activation. In Specific Aim 1, we will focus on the characterization of platelet dysregulation in nonsmoking and smoking HIV-infected volunteers undergoing ART. Specific Aim 2 will test key antiretroviral regimens identified in Aim 1 in order to characterize platelet dysregulation and begin to understand the underlying mechanisms. Completion of these R21 exploratory and developmental studies will provide the foundation to pursue future translational studies of the role of platelets in HIV and the design of new therapeutic interventions to reduce HIV-related CVD.