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Why Interferon's Do Not Work
and Boosting the Immune System Does
April 27, 2003

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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