Mentored Scientist Award

Effect of Gluccocorticoids on Innate and Adaptive Immune Responses During HIV Infection

Headshot of Jeffrey Milush, PhD
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Abstract HIV infection is characterized by high plasma viremia, a progressive loss of CD4+ T cells, and most importantly chronic immune activation, all of which likely contribute to immune dysfunction and disease progression. Although the mechanism(s) resulting in chronic immune activation and impaired immune function are not completely understood, it is likely there is a delicate balance between anti-HIV effector functions and aberrant immune activation. A bi-directional communication between the hypothalamic-pituitary-adrenal (HPA) axis and the host's immune system is essential in maintaining immune activation homeostasis. The HPA axis and immune system communicate through a complex series of incompletely understood feedback loops involving steroid hormones and cytokines. The goal of this proposal is to utilize a novel flow cytometric assay to investigate whether chronic immune activation in HIV infection is caused, at least in part, by a dysfunctional neuroendocrine physiology. This study leverages the availability of well-characterized patient specimens and clinical data to assess the interactions of the neuroendocrine and immune systems. Over the course of one year, we will utilize our novel flow cytometric assay to assess glucocorticoid receptor density in different immune cell subsets within healthy and HIV infected individuals. Furthermore, we will assess the relationship between central and immune cell glucocorticoid sensitivity and determine whether levels of immune activation during HIV infection correlate with glucocorticoid receptor density and immune cell sensitivity to glucocorticoids. Pharmaceutical manufacturers are developing selective glucocorticoids that can inhibit inflammation without the deleterious side effects often associated with long-term glucocorticoid administration. Understanding how immune cell glucocorticoid receptor expression and sensitivity are affected by HIV infection compared to healthy subjects may provide novel means to reduce the deleterious effects of chronic immune activation associated with HIV disease progression. I think it is important to indicate that these are investigator-initiated, and funding is based on quality as indicated by confidential scoring.