| Scientists at two Texas universities have discovered
how hepatitis C virus thwarts immune system efforts to eliminate
it. The finding, published online today in "ScienceExpress",
could lead to more effective treatments for liver disease
caused by hepatitis C virus, says author Michael Gale, Jr.,
Ph.D., of University of Texas Southwestern Medical Center
at Dallas. Dr. Gale and coauthor Stanley Lemon, M.D., of University
of Texas Medical Branch at Galveston, are grantees of the
National Institute of Allergy and Infectious Diseases (NIAID).
"Persistent hepatitis C virus (HCV) infection is a major
cause of liver disease worldwide and is the leading reason
for liver transplants in this country," notes NIAID Director
Anthony S. Fauci, M.D. "The most prevalent form of HCV
in the United States is, unfortunately, the least responsive
to available treatments. Moreover, African Americans are even
less responsive to therapy than Caucasians," he adds.
The immune system has many ways to detect and fight off invading
microbes, and microbes have just as many ways to elude and
disarm immune system components. Through a series of experiments
on cells grown in the laboratory, Drs. Gale and Lemon defined
the strategy HCV uses to evade the host's immune response.
As HCV begins to replicate in its human host, it manufactures
enzymes, called proteases, which it requires to transform
viral proteins into their functional forms. The Texas investigators
determined that one viral protease, NS3/4A, specifically inhibits
a key immune system molecule, interferon regulatory factor-3
(IRF-3). IRF-3 orchestrates a range of antiviral responses.
Without this master switch, antiviral responses never begin,
and HCV can gain a foothold and persist in its host.
Next, the scientists searched for ways to reverse the IRF-3
blockade. They applied a protease inhibitor to human
cells containing modified HCV. This prevented the virus from
making functional NS3/4A and restored the cells' IRF-3 pathway.
Follow-up studies have shown that once restored, the immune
response reduced viral levels to nearly undetectable levels
within days, according to Dr. Gale.
The identification of this viral protease-regulated control
of IRF-3 opens new avenues in both clinical and basic research
on hepatitis C, notes Dr. Gale. Until now, scientists had
not considered the possibility that inhibiting this protease
did anything more than halt viral replication. "Now that
we know NS3/4A inhibition essentially restores the host's
immune response to the virus, we can assess hepatitis drug
candidates for this ability as well," Dr. Gale says.
NS3/4A will be a valuable tool in further dissecting the roles
of viral proteases and their host cell targets, says Dr. Gale.
For example, the scientists plan to use NS3/4A to hunt for
the still unknown host cell enzyme responsible for activating
IRF-3. Conceivably, Dr. Gale explains, future therapeutic
approaches to viral disease could involve boosting the activity
of any key host enzymes that are found.
"Understanding the tricks that the hepatitis C virus
employs to impair the immune system represents an important
advance with potential implications for successful cure of
those suffering from liver disease," says Leslye Johnson,
Ph.D., chief of NIAID's enteric and hepatic diseases branch.
NIAID is a component of the National Institutes of Health
(NIH), which is an agency of the Department of Health and
Human Services. NIAID supports basic and applied research
to prevent, diagnose, and treat infectious and immune-mediated
illnesses, including HIV/AIDS and other sexually transmitted
diseases, illness from potential agents of bioterrorism, tuberculosis,
malaria, autoimmune disorders, asthma and allergies.
National Institutes of Health
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