Host Microbe Biology

What Makes Viral Infections Persist and How?

Researchers at the University of Pennsylvania led by Carolina B. Lopez think the answer to the question in the title is DVGs, or defective viral genomes, that occur when a virus replicates so quickly some of its copies don’t contain the right number of genes.  DVGs have long been known to stimulate the immune system and this helps the host clear a viral infection.  Now Lopez and her colleagues have shown that DVGs also stimulate two signaling proteins called TNF 2 and MAVS (mitochondrial anti-viral signaling protein), which help human cells survive viral infections.  MAVS is also called VISA (virus-induced signaling adapter), IPS-1, and Cardif.

If DVGs end up in a cell that doesn’t have the MAVS pathway, the cell dies; but if the cell does have the MAVS pathway, it survives the acute stage of the viral infection with the DVG inside.  That can lead to chronic respiratory problems from respiratory viruses, encephalitis after measles, and persistent Ebola virus that can be passed to another host through body fluids.

“MAVS is engaged during the antiviral response, and only cells that have a lot of DVGs activate this pathway,” said Lopez.  “These data show that our cells are wired to survive if they are engaged in antiviral responses, explaining the paradoxical functions of DVGs.  It seems that, in order to persist, the virus is taking advantage of these host pathways that are there to promote the survival of cells working to eliminate the virus.”

The team’s next step is to conduct in vivo experiments to make sure their findings hold in that setting.  They are also curious about the dual roles of TNF, which may explain why TNF-targeted therapies haven’t always produced expected results.

“I want to see if there’s a way we can harness this pathway to minimize and avoid the persistence of these viruses, which is really relevant if we think about the chronic diseases associated with some of these respiratory viruses,” said Lopez.

Caption: Seemingly acute viral infections can persist in spite of viruses triggering an immune response. Researchers from the University of Pennsylvania found that cells enriched with defective viral genomes, labeled in green, were more likely to survive infection than cells with full-length viral genomes, labeled in yellow-orange.
Credit: University of Pennsylvania
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For more information, go to the October 6 issue of Nature Communications.