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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI108272-05
Application #
9313176
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Chiou, Chen-Chia Christine C
Project Start
2013-08-12
Project End
2018-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Christodoulides, Alexei; Gupta, Neha; Yacoubian, Vahe et al. (2018) The Role of Lipoproteins in Mycoplasma-Mediated Immunomodulation. Front Microbiol 9:1682
Kelesidis, Theodoros; Moser, Carlee B; Johnston, Elizabeth et al. (2018) Brief Report: Changes in Plasma RANKL-Osteoprotegerin in a Prospective, Randomized Clinical Trial of Initial Antiviral Therapy: A5260s. J Acquir Immune Defic Syndr 78:362-366
Seang, Sophie; Kelesidis, Theodoros; Huynh, Diana et al. (2018) Low Levels of Endothelial Progenitor Cells and Their Association with Systemic Inflammation and Monocyte Activation in Older HIV-Infected Men. AIDS Res Hum Retroviruses 34:39-45
Kelesidis, Theodoros; Kendall, Michelle A; Danoff, Ann et al. (2018) Soluble levels of receptor for advanced glycation endproducts and dysfunctional high-density lipoprotein in persons infected with human immunodeficiency virus: ACTG NWCS332. Medicine (Baltimore) 97:e10955
Kelesidis, Theodoros; Tran, Thuy Tien T; Brown, Todd T et al. (2017) 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 22:113-126
Kim, Joseph Y; Kelesidis, Theodoros; Yang, Otto O (2017) Detection of Donor-Derived Microparticles in the Peripheral Blood of a Hand Transplant Recipient During Rejection. Transplant Direct 3:e131
Kelesidis, Theodoros; Schmid, Ingrid (2017) Assessment of Telomere Length, Phenotype, and DNA Content. Curr Protoc Cytom 79:7.26.1-7.26.23
Angelovich, Thomas A; Hearps, Anna C; Oda, Michael N et al. (2017) Dysfunctional high-density lipoprotein from HIV+ individuals promotes monocyte-derived foam cell formation in vitro. AIDS 31:2331-2336
Angelovich, Thomas A; Hearps, Anna C; Maisa, Anna et al. (2017) Quantification of Monocyte Transmigration and Foam Cell Formation from Individuals with Chronic Inflammatory Conditions. J Vis Exp :
Christodoulides, Alexei; Boyadjian, Ani; Kelesidis, Theodoros (2017) Spirochetal Lipoproteins and Immune Evasion. Front Immunol 8:364

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