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The role of dysfunctional High Density Lipoprotein in immune activation and atherosclerosis associated with Human Immunodeficiency Virus Type 1 infection

  • Author(s): Kelesidis, Theodoros
  • Advisor(s): Yang, Otto O
  • et al.
Abstract

With improved survival cardiovascular disease (CVD) has become an increasingly important cause of morbidity and mortality among people with treated HIV-1 infection. HIV-1 infection is characterized by a chronic state of immune activation that is an independent predictor of disease progression. Residual immune activation in treated HIV-1 may be contributing to atherosclerosis but there is limited evidence supporting this hypothesis. The mechanisms that connect inflammation, CVD and activation of the immune system in HIV infection remain to be elucidated. Oxidized lipids may be a significant mediator in the interplay between inflammation, immune activation and atherosclerosis. While normal High Density Lipoprotein (HDL) binds oxidized lipids and protects against CVD, HDL can become oxidized and dysfunctional in the setting of chronic inflammatory diseases. The primary goal of this dissertation is to better define the role of dysfunctional HDL in immune activation and atherosclerosis associated with HIV-1 infection.

This was addressed using a variety of approaches. First we showed that immune activation may be a contributing factor to progression of atherosclerosis in HIV-1 infection. Using a cell based assay of HDL function we found that HIV-1 infected subjects have dysfunctional HDL. We then developed novel cell free biochemical assays that measure redox properties of HDL as tools to demonstrate that HIV-1 infected subjects have dysfunctional HDL that is independently associated with biomarkers of macrophage and T cell activation, and predictors of disease progression. We then investigated the direct in vitro effects of dysfunctional (oxidized) HDL on T cells, which are important for immune activation, HIV-1 immunopathogenesis and atherogenesis. We found that modified dysfunctional HDL directly upregulated markers of T cell activation in vitro, increased T cell proliferation and production of cytokines, specific killing of HIV-1 specific cytotoxic CD8+ T cells (CTLs) and expression of chemokine receptors (CXCR4, CCR5) on CD4+ T cells important for HIV-1 infectivity, whereas it impaired the ability of HIV-1 specific CTLs to suppress HIV-1 replication. Together these results suggest that dysfunctional HDL has a major role in immune activation and atherosclerosis associated with HIV-1 infection.

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