Title : Human Immunodeficiency Virus-1 Tat exerts its neurotoxic effects by downregulating Sonic Hedgehog signaling
HIV-1 can alter the expression of tight junction proteins by downregulating Sonic hedgehog (Shh) signaling, thereby disrupting BBB integrity. In this study, we employed a conditional, CNS specific, transgenic murine model to investigate if Tat, a known neurotoxic HIV protein, is responsible for dysregulation of Shh signaling. Results indicate that Tat+ mice exhibit reduced expression of Shh, Gli-1 and Smoothened proteins. Tat+ mice also express lower levels of tight junction protein Claudin-5 and higher levels of adhesion protein Vcam-1. As a result of these BBB alterations significantly higher numbers of leukocytes infiltrate into the CNS of Tat+ mice as compared to Tat- mice. Administration of Smoothened agonist (SAG), a Shh mimetic, significantly reduced the number of brain-infiltrating leukocytes (BILs) in Tat+ mice. Further, our in vitro experiments using human brain microvascular endothelial cells suggest that pharmacological induction of Shh signaling can rescue detrimental effects of Tat on endothelial function by inducing the expression of junctional proteins and by decreasing the levels of inflammatory cytokines/chemokines such as CCL2, IL-1? and IL-6. Overall, this study identifies a novel mechanism by which HIV-1 Tat exerts its neurotoxic effects as well as underscores the neuroprotective role of Shh signaling in adult brain. Findings from this study can be used to devise potential therapeutic approaches to alleviate HIV associated neuropathogenesis.