Integrated Regulatory Mechanisms Controlling HIV-Associated Immune Activation
Chronic immune activation is a significant determinant of HIV-mediated CD4+ T cell loss and disease progression. Despite effective viral suppression, chronic inflammation persists at levels higher than in uninfected people, yet the inflammatory stimuli and the mechanisms by which inflammation persists and promotes disease pathology are not completely understood. Many mechanisms likely contribute to chronic immune activation including persistent antigenemia, depletion of T regulatory cells (Tregs), and stimulation of toll-like receptors. Additionally, chronic stress may have a significant impact on disease progression through its activation of the hypothalamo-pituitary-adrenal (HPA) axis. Chronic stress can alter glucocorticoid (i.e. cortisol) secretion leading to glucocorticoid resistance and decreased ability to regulate inflammatory signals. Furthermore, abnormal glucocorticoid signaling can directly and indirectly affect the production and function of Tregs that may also contribute to enhanced immune activation. The goal of this proposal is to investigate the interaction of the HPA axis, Treg subsets and immune activation to further elucidate the sources of inflammation in both untreated and antiretroviral treated (ART) subjects. We will perform a longitudinal study of 40 HIV-infected subjects not currently on ART to assess how changes in HPA axis function and Treg frequencies influence immune activation and disease progression over time. Next, we will investigate how Tregs and the HPA axis contribute to the residual immune activation present during ART. Hypothesis driven and exploratory statistical measures including linear regression models, repeated measures models, and Pearson and rank correlations will be used to investigate relationships between immune activation, HPA axis function and Treg frequencies. We anticipate that data collection and analyses will be completed in 8-10 months, and will provide critical preliminary data for a R01 application to assess the impact of stress, HPA axis function and T regulatory cell function in HIV pathogenesis.