Activation of the Anti-Oxidative Stress Response Reactivates Latent HIV-1 Through the Mitochondrial Antiviral Signaling Protein Isoform MiniMAVS

Indra Sarabia, Camille L. Novis, Amanda B. Macedo, Hiroshi Takata, Racheal Nell, Juyeon C. Kakazu, Robert L. Furler, Binita Shakya, Heidi L. Schubert, Christopher P. Hill, Ana Beatriz DePaula-Silva, Adam M. Spivak, Lydie Trautmann, Vicente Planelles, Alberto Bosque

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)682182
Number of pages1
JournalFrontiers in immunology
Volume12
DOIs
StatePublished - 2021

Keywords

  • Dynasore
  • HIV-1
  • MAVS
  • anti-oxidative stress response
  • latency
  • latency-reversal agents
  • reactive oxygen species
  • shock and kill

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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