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

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.

Host Cell Redox Alterations Promote Latent HIV-1 Reactivation through Atypical Transcription Factor Cooperativity

“…Together, the data suggest that EPH334-induced ROS production partly mediates latent HIV-1 gene expression, which is potentially consistent with recent reports linking antioxidative stress responses with latent HIV-1 reactivation [ 53 ].…”

Connection Between HIV and Mitochondria in Cardiovascular Disease and Implications for Treatments

“…Oxidative stress, which is a hallmark of HIV, may bridge together these HIV-related bioenergetic changes in immune cells. 62 Oxidative stress is an independent predictor of all-cause mortality in HIV. 63 While CVD is known to be influenced by oxidative stress, it remains unclear to what extent HIV-mediated oxidative stress and changes in bioenergetics affect adverse cardiovascular outcomes.…”

“…Finally, shorter isoforms of the MAVs, known as miniMAVS, can have differential effects from regular MAVs, mainly in antioxidative stress responses, which may reactivate latent HIV-1, suggesting the capability for shock-and-kill strategies for HIV-1 eradication. 62 Yet, the mitochondrial context of these MAV forms remains poorly understood.…”

Analogs of the Catechol Derivative Dynasore Inhibit HIV-1 Ribonuclease H, SARS-CoV-2 nsp14 Exoribonuclease, and Virus Replication

“…Also, dynasore induced NF-κB and IFN-β pathways by activation of mitochondrial antiviral signaling protein (MAVS) based on ROS (reactive oxygen species) formation and Rac1 upregulation [ 38 ]. In this instance, however, dynasore reactivated latent HIV-1 by activation of miniMAVS isoforms upon induction of antioxidative stress response [ 39 ]. A notable property of dynasore is that its chemical synthesis is relatively simple, starting from commercially available compounds, which also enables the preparation of a large series of analogs for biological testing and activity optimization.…”