Alprazolam Prompts HIV-1 Transcriptional Reactivation and Enhances CTL Response Through RUNX1 Inhibition and STAT5 Activation

Frontiers in Neurology

卷:12

Weam Othman Elbezanti¹  Zachary Klase²  Adel Ahmed³  Simon Cocklin³  Rachel Van Duyne⁵  Angel Lin⁵  Alexis Schirling⁶ 

[1] Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, United States;

[2] Center for Neuroimmunology and CNS Therapeutics, Institute of Molecular Medicine and Infectious Diseases, Drexel University College of Medicine, Philadelphia, PA, United States;

[3] Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, United States;

[4] Department of Biological Sciences, University of the Sciences, Philadelphia, PA, United States;

[5] Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, United States;

[6] HIV-1 Dynamics and Replication Program, National Cancer Institute, Frederick, MD, United States;

关键词: HIV-1;    latency;    alprazolam;    stat5;    latency reversing agent;    runx1;   

DOI  :  10.3389/fneur.2021.663793

来源: DOAJ

【 摘 要 】

The HIV-1 pandemic is a significant challenge to the field of medicine. Despite advancements in antiretroviral (ART) development, 38 million people worldwide still live with this disease without a cure. A significant barrier to the eradication of HIV-1 lies in the persistently latent pool that establishes early in the infection. The “shock and kill” strategy relies on the discovery of a latency-reversing agent (LRA) that can robustly reactivate the latent pool and not limit immune clearance. We have found that a benzodiazepine (BDZ), that is commonly prescribed for panic and anxiety disorder, to be an ideal candidate for latency reversal. The BDZ Alprazolam functions as an inhibitor of the transcription factor RUNX1, which negatively regulates HIV-1 transcription. In addition to the displacement of RUNX1 from the HIV-1 5′LTR, Alprazolam potentiates the activation of STAT5 and its recruitment to the viral promoter. The activation of STAT5 in cytotoxic T cells may enable immune activation which is independent of the IL-2 receptor. These findings have significance for the potential use of Alprazolam in a curative strategy and to addressing the neuroinflammation associated with neuroHIV-1.

【 授权许可】

Unknown