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 Institute of Health
