Platelet activation by cocaine in HIV-1 patients involves IKK

University Of Rochester, Rochester NY

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Abstract

DESCRIPTION (provided by applicant): The increased incidence of thrombotic complications in human immunodeficiency virus type-1 (HIV) infected populations, despite adequate control of the virus with combination antiretroviral therapy (cART), remains a significant clinical concern. These thrombotic complications, which can include atherosclerosis, venous thromboembolism (VTE), and myocardial infarction, are further exacerbated by cocaine use among HIV infected individuals. Cocaine abuse alone is well known to have multiple harmful effects on the cardiovascular system. Platelets, which are small, anucleate, circulating blood cells that are known to be critical for the process of thrombosis and have recently been shown to contribute to inflammatory disorders such as atherosclerosis, likely play a central role in these HIV/cocaine-induced thrombotic complications. Our lab, and others, have demonstrated that HIV infection is associated with increased levels of molecules known to activate platelets, including soluble CD40 ligand (sCD40L), and platelet activating factor (PAF). Additionally, several studies have shown impaired platelet function and increased platelet activation during HIV infection, and thrombocytopenia is a platelet-related abnormality that is frequently associated with HIV infection. Consistent with this, elevated levels of platelet activation have been detected in HIV positive patients currently receiving cART. Recent reports have shown that inhibitors targeting IKK and other components of the NF-?B pathway can impair platelet activation and function, thus suggesting a non-transcriptional, yet critical role for IKK in platelets. The lack of informaton on the regulation of platelet activation and function in HIV-infected individuals that also abuse cocaine, presents a critical barrier in treating the thrombotic complications that are common in this population. Based on the ability of HIV and cocaine to enhance platelet activation, and the importance of NF-?B signaling intermediates for platelet function, we hypothesize that IKK activation is central for platelet activation induced by HIV and cocaine. Accordingly, molecular mechanisms underlying the thrombotic complications that are common among HIV-infected individuals that also abuse cocaine will be investigated. The intracellular signaling events that trigger aberrant platelet activation in these individuals will be examined by employing robust experimental models in which HIV virions and viral proteins, as well as cocaine, will be added to platelets in order to define platelet activation levels and IKK activation status in a manner that s physiologically relevant.