Hepatitis C tricks liver cells to sabotage immune defenses

The virus that causes hepatitis C protects itself by blocking signals that drive elements of liver cells’ immune defenses, University of Washington researchers report in a new study.

“The finding helps explain why many patients fail certain drug treatments, and should help develop more effective alternate treatment protocols,” said Ram Savan, a UW assistant professor of immunology and the study's corresponding author.

Hepatitis C virus is the most common cause of chronic hepatitis and the leading U.S. cause of liver cancer. It is primarily spread through contact with infected blood. Each year, more than 30,000 Americans become infected and as many as 85 percent develop life-long chronic infections. Of these patients, about one in 10 will eventually develop cirrhosis and liver cancer.

Ram Savan is a UW assistant professor of immunology.

In the new study, lead author Abigail Jarret, now a graduate student at Yale University, and colleagues showed that hepatitis C virus sabotages liver cell antiviral defenses by blunting the effect of key immune proteins called interferons.

When cells become infected, they release interferons, which in turn spur hundreds of genes that generate virus-fighting proteins within the cell. Interferons can even cause cells to self-destruct to prevent the virus from propagating.

One of these interferons, called interferon-alpha, has been used for many years to treat chronic hep C virus infections, either alone or in concert with an antiviral called ribavirin. These treatments helped many patients clear their virus, but the treatment fails to cure more than 60 percent of patients.

Newer, more effective drugs with fewer side effects have now largely replaced interferon-based therapies. However it was not clear why interferon treatment failed so often. In their study, the UW researchers hypothesized that the virus' ability to evade interferons was related to the cells themselves.

In a previous study, Savan’s research team discovered that when hepatitis C virus invades a liver cell, the virus induces the cell to activate two genes -- MYH7 and MYH7B -- that are usually active only in smooth skeletal muscle and cardiac cells. Once activated, these genes produced two microRNAs, molecules that can interfere with the production of other proteins. Savan and colleagues showed that these microRNAs interfered with the cell’s production of two interferons. Thus, by activating the MYH7 and MYH7B genes, the invading hep C viruses limit liver cells' ability to generate these interferons and blunt the cells’ ability to resist and clear the virus.

In the new study, published today in Nature Medicine, the investigators showed that these virally-induced microRNAs also inhibit production of a receptor crucial to the cell's interferon-driven antiviral response.

Thus, these hepatitis C virus-induced microRNAs can blunt liver cell interferon-driven antiviral defenses in two ways, Jarret explained. First, the virus inhibits the cell’s ability to produce its own type III interferons, and, second, it prevents the cells from making the receptors needed in order for type I interferons to be effective. “This may in part explain why interferon treatments, which harness a type I interferon, fail in so many patients,” Jarret said.

This project was funded partly by the National Institutes of Health (AI108765, AI060389, AI40035, CA148068, HHSN261200800001E).