Combination antiretroviral therapy (cART) is appropriately credited with dramatically curbing the AIDS pandemic and is increasingly being used as a prophylactic treatment to prevent HIV transmission among ?at high-risk? populations. Despite these therapeutic advances, HIV infection is associated with a number of co-morbid conditions, the most notable of which is a spectrum of neurocognitive disorders termed HIV Associated Neurodegenerative Disorders (HAND). The contribution of HIV vs. cART on HAND is not clear. cART, independent of HIV, may negatively impact cells of the Central Nervous System (CNS). While some studies demonstrated direct neurotoxic effects of cART, little is known about their impact on macro and micro glial cells (e.g. astrocytes and microglia/macrophages, respectively). Glial cells coordinate immunologic responses and communication with neurons and endothelial cells. Dysregulation of glial cells is associated with a number of neurodegenerative diseases, including HAND. In this application, in Aim 1 we will determine the impact of cART (Atripla and Triumeq) on the phenotype and function of astrocytes, microglia, and monocyte- derived macrophages (MDMs).
In Aim 2, we will determine the impact of cART on glia and neuroinflammation in vivo humanized mice. Collectively, these studies will reveal the impact of cART on glial cells and its subsequent effects on neuronal health and blood brain barrier integrity as well as inform combination of antiretrovirals that will retain therapeutic efficacy with minimal CNS dysregulation.
In the last several decades, the landscape of HIV has shifted from a non-survivable disease to a treatable chronic condition analogous to diabetes or high blood pressure. This was made possible by the advent of antiretroviral drugs. However, similar to other drugs, antiretrovirals are not without adverse effects. In this application, we will study the effect of antiretroviral drugs on brain cells known as glia. Our studies will inform future combinations of antiretrovirals that maintain efficacy with minimal adverse effects.
