Viral Strategy Uses Mitochondrial Remodeling to Evade Immune Response and Identify New Drug Opportunities

Researchers at The Wistar Institute have uncovered a novel mechanism employed by certain viruses to manipulate mitochondrial architecture, effectively silencing the host's immune response and facilitating viral replication. Published in Nature Microbiology, the study reveals how the viral protein vBcl-2, associated with Kaposi's sarcoma-linked herpesvirus (KSHV), exploits a host enzyme, NM23-H2, to induce mitochondrial fragmentation. This structural change prevents the formation of the MAVS signaling platform, a crucial component for antiviral defense mechanisms like Type I interferon production.

Traditionally known for its role in inhibiting cell death, vBcl-2 was found to have a more sophisticated function: remodeling mitochondria during a specific phase of the viral lifecycle. By activating NM23-H2, vBcl-2 promotes mitochondrial fission, disrupting immune signaling and enabling the virus to complete its late-stage assembly and exit the cell.

This process effectively destabilizes the immune response, preventing the activation of key antiviral proteins such as TRIM22 and MxB, which normally trap viral particles and inhibit their release. Furthermore, the team identified a small molecule, VBNI-1, capable of interfering with the vBcl-2 and NM23-H2 interaction. VBNI-1 successfully blocked mitochondrial fission and restored immune signaling pathways in laboratory models without harming uninfected cells, marking it as a promising candidate for targeted antiviral therapy.

The discovery highlights a potential new therapeutic target—the virus-induced mitochondrial remodeling process—and opens avenues for drug development against KSHV and other herpesviruses that may employ similar tactics. This interdisciplinary research underscores the importance of understanding virus-host interactions at the cellular level, paving the way for innovative treatments for virus-associated diseases.

For more details, see the full study here.