Hepatitis C virus (HCV) is a worldwide public health problem. The World Health Organization estimates that 170 million people worldwide are chronically infected and that between 3-4 million are newly infected annually. HCV is the leading cause of chronic liver disease including hepatic fibrosis, end-stage cirrhosis, and hepatocellular carcinoma. There is no vaccine available to prevent HCV, and current therapies are costly, have serious side effects and are curative in only a fraction of patients. According to the World Health Organization, the major causes of HCV infection are use of unscreened blood transfusions, and re-use of needles and syringes that have not been adequately sterilized.
Viral infections like hepatitis C often trigger an immediate innate immune response involving release of type 1 interferon (IFN-? and IFN-?). In turn, type 1 interferon stimulates the production of a family of what are known as IFN stimulated genes that have a multitude of inhibitory effects on viral replication in infected and neighboring uninfected cells. While interferon production and other immune responses can greatly influence the course of a number of different viral infections, many human pathogenic viruses have evolved distinct strategies to inhibit the early signaling events leading to interferon production. HCV is no different.
"We have previously demonstrated that many interferon stimulated genes with antiviral activity are induced in the liver during HCV infection," said Francis V. Chisari, M.D., a Scripps Research professor whose laboratory conducted the study. "Despite their induction, the virus can persist indefinitely, indicating that it is resistant to their antiviral effects."
The current study sheds light on one strategy the hepatitis C virus uses to resist the immune system. The findings suggest that the hepatitis C virus inhibits the activity of naturally occurring interferon by shutting down a key antiviral signaling protein.
Early after HCV infection, the immune system responds to viral RNA by activating a signaling cascade in the infected cells that results in the production of type 1 interferon. One of the intermediaries in that cascade is a mitochondrial antiviral signaling protein (MAVS). HCV blocks the production of type1 interferon by using its protease activity to destroy MAVS. By preventing infected cells from producing interferon, the virus inhibits the body's immune response against HCV, enabling it to persist.
"Our new work shows that HCV does not induce interferon-? or antiviral interferon stimulated genes in the infected cells," Chisari said. "This means that the antiviral interferon stimulated genes expressed in the HCV-infected liver are likely produced by uninfected cells in some novel fashion and that the virus has other tricks up its sleeve that makes it resistant to their antiviral effects. Further study is needed to understand which cells in the liver produce the interferon and how the virus can resist the broad spectrum of these antiviral effects."
The knowledge gained from fundamental studies such as these could lay the groundwork for the development of potential new treatment strategies for this devastating global disease.
Other Scripps Research scientists involved in the study were Guofeng Cheng, Ph.D., and Jin Zhong, Ph.D., postdoctoral fellows in the Chisari laboratory.
The study was supported by the National Institutes of Health.
About The Scripps Research Institute
The Scripps Research Institute, headquartered in La Jolla, California, in 18 buildings on 40 acres overlooking the Pacific Ocean, is one of the world's largest independent, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel.
Scripps Florida, a 364,000 square-foot, state-of-the-art biomedical research facility, will be built in Palm Beach County. The facility will focus on basic biomedical science, drug discovery, and technology development. Palm Beach County and the State of Florida have provided start-up economic packages for development, building, staffing, and equipping the campus. Scripps Florida now operates with approximately 160 scientists, technicians, and administrative staff at 40,000 square-foot lab facilities on the Florida Atlantic University campus in Jupiter.
Journal
Proceedings of the National Academy of Sciences