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Key to Hepatitis Virus Persistence Found
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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 Lesyle 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.
Reference: E Foy, et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease.
Science, April 17, 2003. DOI 10.1126/science.1082604.
Making and Breaking an Antiviral Response
Viral infection activates type I interferon genes. This process requires the cooperative activation of several transcription factors, including interferon regulatory factor (IRF)-3 and IFR-7. Signals such as double-stranded RNA lead to the phosphorylation of IRF-3 and IRF-7 by a yet-uncharacterized virus-activated kinase (VAK). Sharma et al. now show that the component of VAK responsible for IRF-3 and IRF-7 phosphorylation is IKK/TBK-1, an IKK-related kinase. Foy et al. observed that the hepatitis C virus (HCV) serine protease (NS3/4A) blocks IFR-3 phosphorylation. Thus, HCV has evolved a mechanism of obstructing the cellular interferon response, potentially through the proteolytic cleavage of IKK/TBK-1.
Published online April 17, 2003 Science
Abstracts
Regulation of Interferon Regulatory Factor-3 by the Hepatitis C Virus Serine Protease
Eileen Foy 1, Kui Li 2, Chunfu Wang 1, Rhea Sumpter Jr. 1, Masanori Ikeda 2,
Stanley M. Lemon 2, Michael Gale Jr. 1*
1 Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9048,USA.
2 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1019, USA.
* To whom correspondence should be addressed. E-mail: Michael.Gale@UTSouthwestern.edu.
Persistent infections with hepatitis C virus (HCV) are likely to depend on viral inhibition of host defenses. We show that the HCV NS3/4A serine protease blocks the phosphorylation and effector action of interferon regulatory factor-3 (IRF-3), a key cellular antiviral signaling molecule. Disruption of NS3/4A protease function by mutation or a ketoamide peptidomimetic inhibitor relieved this blockade and restored IRF-3 phosphorylation after cellular challenge with an unrelated virus. Furthermore, dominant-negative or constitutively active IRF-3 mutants, respectively, enhanced or suppressed HCV RNA replication in hepatoma cells. Thus, the NS3/4A protease represents a dual therapeutic target, the inhibition of which may both block viral replication and restore IRF-3 control of HCV infection.
Triggering the Interferon Antiviral Response Through an IKK-Related Pathway
Sonia Sharma 1, Benjamin R. tenOever 1, Nathalie Grandvaux 1, Guo-Ping Zhou 1,Rongtuan Lin 2*, John Hiscott 2*
1 Lady Davis Institute for Medical Research-Jewish General Hospital, Departments of Microbiology and
Immunology and Medicine, McGill University, Montreal, Canada H3T 1E2.
2 Lady Davis Institute for Medical Research-Jewish General Hospital, Departments of Microbiology and Immunology and Medicine, McGill University, Montreal, Canada H3T 1E2; Address for correspondence:
Lady Davis Institute for Medical Research, 3755 Cote Ste. Catherine, Montreal, Quebec H3T 1E2, Canada.
* To whom correspondence should be addressed. E-mail:
rongtuan.lin@mcgill.ca john.hiscott@mcgill.ca.
Rapid induction of type I interferon expression, a central event in establishing the innate antiviral response, requires cooperative activation of numerous
transcription factors. Although signaling pathways that activate the transcription factors NF-B and ATF-2/c-Jun have been well characterized, activation of the interferon regulatory factors (IRF)-3 and IRF-7 has remained a critical missing link in understanding interferon signaling. We report that the IB kinase(IKK)-related kinases--IKK and TANK-binding kinase 1--are components of the virus-activated kinase that phosphorylate IRF-3 and IRF-7. These studies
illustrate an essential role for an IKK-related kinase pathway in triggering the host antiviral response to virus infection.
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