Hepatitis C virus is the most common cause of chronic hepatitis and
the leading cause of liver cancer in the United States. It is primarily
spread through contact with infected blood. Each year, more than 30,000
Americans become infected. As many as 85% develop life-long
chronic infections. Of these patients, about one in 10 will eventually
develop cirrhosis and liver cancer.
The virus that causes hepatitis C protects itself by blocking signals
that call up immune defenses in liver cells, revealed University of
Washington researchers and colleagues. The findings are published in Nature Medicine
‘Hepatitis C virus protects itself by blocking signals that call up immune defenses in liver cells.’
"The finding helps explain why many patients fail certain drug
treatments, and should help develop more effective alternate treatment
protocols," said Ram Savan, the study's corresponding author and an
assistant professor of immunology in the UW School of Medicine.
In the latest study, lead author Abigail Jarret, now a graduate
student at Yale University, and her group showed that hepatitis C virus
sabotages the antiviral defenses of liver cells by blunting the effect
of key immune proteins called interferons.
When cells become infected, they release interferons. These in turn
spur hundreds of genes that generate virus-fighting proteins within the
cell. Interferons can even provoke 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 hepatitis C virus infections, either alone
or in concert with an antiviral called ribavirin. These treatments
helped many patients get rid of the virus, but the treatment fails to
cure more than 60% 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. From this study, 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. These genes are usually active
only in smooth skeletal muscle and heart cells. Once activated, these
genes produce two microRNAs, molecules that can interfere with the
production of other proteins.
Savan and his fellow researchers showed that these microRNAs
interfered with the cell's production of two interferons. By activating
the MYH7 and MYH7B genes, the invading hepatitis C viruses limit liver
cells' ability to generate these interferons. The cells are then less
able to resist and remove the virus.
The investigators also showed that these virally-induced microRNAs
inhibit production of a receptor crucial to the cell's interferon-driven
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.
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.