Cardiovascular disease (CVD) is becoming a major cause of death in persons with HIV-1 infection. The mechanisms that link HIV-1 infection, CVD and activation of the immune system associated with HIV infection (immune activation) remain unknown. High density lipoproteins (HDL) have key roles in moderating inflammation and immunity. HDL has generally protective effects against oxidized lipids and CVD, and has a normal potent antioxidant role. However, HDL is subject to continuous remodeling in vivo and during systemic inflammation it can be oxidized, lose its normal antioxidant functions, and become dysfunctional and pro-oxidant. We have recently shown that HIV-1 infected subjects have dysfunctional HDL that increases monocyte chemotaxis, a key event in atherogenesis, in vitro and that also is significantly associated with biomarkers of T cell activation and progressio of atherosclerosis in HIV-infected subjects. Therefore, a study to assess dysfunctional HDL as a possible mechanistic link and a new contributor to the increased rate of immune activation and CVD in HIV-1 infection is a novel approach in this patient population. This award application is intended to support the applicant's clinical scientist research career development award through mentoring, formal training in immunology, virology, lipidology and biostatistics. We hypothesize that a vicious cycle of HIV-induced immune activation, inflammation, production of oxidized HDL, and further immune activation may explain the increased rate of CVD in HIV infection. To test this hypothesis, we will determine the mechanisms that mediate the cross-talk between oxidized HDL and cells important for HIV-induced immune activation and atherogenesis (Aim 1). Previously published data have demonstrated HDL may have antiviral activity and that oxidized lipids may directly modulate immunity and affect HIV infectivity. In view of these data, in Aim 2, we will investigate whether oxidized HDL directly affects the life cycle of HIV-1 and leads to reduced antiviral responses of cytotoxic CD8 T cells and increased viremia that drives immune activation and inflammation. Finally, guided by our preliminary findings that administration of a drug that can mimic the function of normal HDL (HDL mimetic) may improve HDL function in vitro in HIV-1 infected subjects, we will investigate whether in vitro administration of HDL mimetics, can reduce HIV-induced immune activation and HIV-1 infectivity (Aims 1, 2). The data to be generated in the proposed study will allow to determine whether oxidized HDL is a novel mechanistic link between HIV-1, immune activation and atherosclerosis. The long-term goals of this research are to provide the foundation for further studies whether HDL mimetics can be used therapeutically in HIV infection.
HIV-infected patients receiving antiviral therapy die prematurely of cardiovascular disease (CVD), compared to the general population but the mechanisms that link HIV infection, CVD and activation of the immune system (immune activation) remain unknown. This research proposal is designed to investigate whether abnormal lipoproteins that are produced during systemic inflammation seen with HIV infection may mediate the cross-talk between HIV, the immune system and CVD. We anticipate that this 5-year study will improve our understanding of the pathogenesis of HIV-associated immune activation and CVD and these findings may initiate further studies to explore the efficacy of novel therapeutic interventions that might improve the prognosis of HIV-infected patients.
|Kelesidis, Theodoros; Jackson, Nicholas; McComsey, Grace A et al. (2016) Oxidized lipoproteins are associated with markers of inflammation and immune activation in HIV-1 infection. AIDS 30:2625-2633|
|Kelesidis, Theodoros; Tran, Thuy Tien T; Brown, Todd T et al. (2016) Changes in plasma levels of oxidized lipoproteins and lipoprotein subfractions with atazanavir-, raltegravir-, darunavir-based initial antiviral therapy and associations with common carotid artery intima-media thickness: ACTG 5260s. Antivir Ther :|
|Kelesidis, Theodoros; Papakonstantinou, Vasiliki; Detopoulou, Paraskevi et al. (2015) The Role of Platelet-Activating Factor in Chronic Inflammation, Immune Activation, and Comorbidities Associated with HIV Infection. AIDS Rev 17:191-201|
|Kelesidis, Theodoros; Currier, Judith S (2014) Dyslipidemia and cardiovascular risk in human immunodeficiency virus infection. Endocrinol Metab Clin North Am 43:665-84|
|Kelesidis, Theodoros; Currier, Judith S; Yang, Otto O et al. (2014) Role of RANKL-RANK/osteoprotegerin pathway in cardiovascular and bone disease associated with HIV infection. AIDS Rev 16:123-33|