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

Authors

Irfan A. Khan, Department of Basic and Clinical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, 12208, USA.
Arthur H. Worrad, Department of Basic and Clinical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, 12208, USA.
Meera V. Singh, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Sanjay B. Maggirwar, Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington, DC, 20052, USA.
Vir B. Singh, Department of Basic and Clinical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, 12208, USA. Vir.Singh@acphs.edu.

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.

APA Citation

Khan, Irfan A.; Worrad, Arthur H.; Singh, Meera V.; Maggirwar, Sanjay B.; and Singh, Vir B., "Human immunodeficiency virus-1 Tat exerts its neurotoxic effects by downregulating Sonic hedgehog signaling" (2022). GW Authored Works. Paper 139.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/139

Department

Microbiology, Immunology, and Tropical Medicine