1. Activation of the Anti-Oxidative Stress Response Reactivates Latent HIV-1 Through the Mitochondrial Antiviral Signaling Protein Isoform MiniMAVS.
- Author
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Sarabia I, Novis CL, Macedo AB, Takata H, Nell R, Kakazu JC, Furler RL, Shakya B, Schubert HL, Hill CP, DePaula-Silva AB, Spivak AM, Trautmann L, Planelles V, and Bosque A
- Subjects
- Biomarkers, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes virology, Humans, Models, Biological, NF-kappa B metabolism, Oxidative Stress, Reactive Oxygen Species, Signal Transduction drug effects, HIV Infections immunology, HIV Infections metabolism, HIV Infections virology, HIV-1 physiology, Host-Pathogen Interactions immunology, Mitochondrial Proteins metabolism, Virus Activation immunology, Virus Latency immunology
- Abstract
The mitochondrial antiviral signaling protein (MAVS) is part of the cell's innate immune mechanism of defense. MAVS mRNA is bicistronic and can give rise to a full length-MAVS and a shorter isoform termed miniMAVS. In response to viral infections, viral RNA can be sensed by the cytosolic RNA sensors retinoic acid-inducible gene I (RIG-I) and/or melanoma differentiation-associated protein 5 (MDA5) and activate NF-κB through interaction with MAVS. MAVS can also sense cellular stress and activate an anti-oxidative stress (AOS) response through the activation of NF-κB. Because NF-κB is a main cellular transcription factor for HIV-1, we wanted to address what role MAVS plays in HIV-1 reactivation from latency in CD4 T cells. Our results indicate that RIG-I agonists required full length-MAVS whereas the AOS response induced by Dynasore through its catechol group can reactivate latent HIV-1 in a MAVS dependent manner through miniMAVS isoform. Furthermore, we uncover that PKC agonists, a class of latency-reversing agents, induce an AOS response in CD4 T cells and require miniMAVS to fully reactivate latent HIV-1. Our results indicate that the AOS response, through miniMAVS, can induce HIV-1 transcription in response to cellular stress and targeting this pathway adds to the repertoire of approaches to reactivate latent HIV-1 in 'shock-and-kill' strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sarabia, Novis, Macedo, Takata, Nell, Kakazu, Furler, Shakya, Schubert, Hill, DePaula-Silva, Spivak, Trautmann, Planelles and Bosque.)
- Published
- 2021
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