Title

Human immunodeficiency virus-1 Tat exerts its neurotoxic effects by downregulating Sonic hedgehog signaling

Document Type

Journal Article

Publication Date

2-18-2022

Journal

Journal of neurovirology

DOI

10.1007/s13365-022-01061-8

Keywords

Blood–brain barrier; HAND (HIV-associated neurocognitive disorder); HIV-Tat; Neuroinflammation; Sonic hedgehog

Abstract

We previously showed that HIV-1 can alter the expression of tight junction proteins by downregulating Sonic hedgehog (Shh) signaling, thereby disrupting blood-brain barrier (BBB) integrity. In this study, we employed a conditional, CNS specific, Tat transgenic murine model to investigate if HIV-Tat exerts its neurotoxic effects by downregulating Shh signaling. Results indicate that Tat + mice exhibit significantly reduced expression of Shh and Gli1. HIV-Tat induced downregulation of Shh signaling correlated with disruption of BBB function and induced infiltration of peripheral leukocytes into the brain tissue. Further, our in vivo and in vitro experiments suggest that activation 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.

Department

Microbiology, Immunology, and Tropical Medicine

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