A series of studies by researchers at University of Texas ( UT ) Southwestern Medical Center sheds light on the mechanisms used by viruses to thwart host’s immune defenses and may aid in the development of more effective drugs to fight hepatitis C and West Nile viruses, as well as the flu and the common cold.

In a study, published in the Journal of Virology, UT Southwestern researchers describe how an essential gene, called RIG-I, turns on a cascade of host immune defenses when the hepatitis C virus ( HCV ) replicates in cultured human cells.

Those immune defenses should fight off the virus, but in a separate study, in the Proceedings of the National Academy of Sciences ( PNAS ), the researchers show how HCV sidesteps the immune response, allowing the virus to replicate unchecked.

Michael Gale, at UT Southwestern and senior author of the two studies, said the tactics employed by HCV to infect a host are likely to be similar to those employed by other RNA viruses such as West Nile, influenza and the common cold.

“It’s a battle between viruses and humans. Viruses have co-evolved with their hosts, so every time we have evolved a gene with a new function that allows us to fight off a virus, the virus adapts and comes up with a new function of its own to counteract our defenses,” Gale says.

In the Virology paper, Gale and his research group found that a specific mutation in the gene RIG-I conferred permissiveness to HCV, allowing it to replicate “like gangbusters” in those cells with the mutation.
Researchers determined that the protein made by the gene is essential to turning on signals that tell the cell to mount an immune response. Cells with the mutated RIG-I protein were unable to initiate immune signals, abolishing the host cells’ defenses to HCV.

When HCV infects a cell, the RIG-I protein physically binds the virus genetic material. RIG-I then changes its shape, which sends a cascade of signals to other proteins to activate a transcription factor called interferon regulatory factor 3 ( IRF-3 ). This protein turns on the genes responsible for producing interferon, which neutralizes viruses by suppressing their replication.

The researchers also investigated why cells with functioning RIG-I protein still had persistent HCV infection. In the study in PNAS, Gale and his group found an explanation for HCV’s tenaciousness.

Once HCV infects the cell, it launches a counterattack against RIG-I, producing a protein called a protease to disrupt the cell’s immune response that is otherwise turned on through RIG-I by the virus infection. The viral protease, NS3/4A, chops up essential signaling proteins involved in carrying RIG-I’s message to IRF-3. Without those signals, IRF-3 can’t turn on the genes to make interferon, and the virus continues to replicate unimpeded.

“Having identified RIG-I, now we can spend our time completely defining the signaling pathway that goes from RIG-I all the way down to IRF-3,” Gale said. “ Once we’ve done that, we hope to identify parts of the pathway to target with drugs to try to limit infection.”

Drugs called protease inhibitors currently are used to treat patients infected with HIV and have also shown promise in treating hepatitis C patients in experimental trials.

“ We now know that treating patients with a protease inhibitor will prevent the viral protease from cutting up the signaling proteins,” Gale said. “ We’re currently working to identify exactly what proteins the viral protease is attacking, which could help toward further developing the protease inhibitors and more effective therapies for hepatitis C and possibly other viral infections.”

A third paper, also published in PNAS, describes collaborative research with a group at UT Medical Branch in Galveston. The findings shed light on how HCV disrupts a separate immune pathway in infected liver cells, again by unleashing the NS3/4A protease to cleave another protein essential to triggering immune defenses. Again they found that protease inhibitors could reverse the effects of NS3/4A, allowing this immune pathway to be restored to shut down HCV replication.

Source: UT Southwestern Medical Center, 2005


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