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Study details hepatitis C ability to block immune system response
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Findings could influence approaches to treatment and outcome
The study was published in an advance online edition of the Proceedings of the National Academy of Sciences on May 17.
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.
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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.
Published online before print May 17, 2006
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0602957103
Microbiology
Inhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -independent mechanisms
( IFN-stimulated genes | nonstructural protein 3/4A | retinoic acid-induced gene I )
Guofeng Cheng, Jin Zhong, and Francis V. Chisari *
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037
Contributed by Francis V. Chisari, April 11, 2006
Abstract
The recent establishment of a robust hepatitis C virus (HCV) cell culture system permits analysis of virus-host interactions during HCV infection. Here, we report that HCV genotype 2a (JFH-1) infection fails to induce IFN-beta or IFN-stimulated gene expression in Huh-7 cells, and that it blocks IFN-beta and IFN-stimulated gene production after transfection of synthetic dsRNA. Overexpression of individual components of the dsRNA-signaling pathway in HCV-infected and uninfected cells indicates that HCV inhibits IFN- promoter activity by inactivating the mitochondrial antiviral signaling protein/IFN-beta promoter stimulator 1 (MAVS/IPS-1), while leaving the IFN-induced Janus kinases-signal transducers and activators of transcription (JAK-STAT) signaling pathway intact. We also show that MAVS/IPS-1-dependent IFN-beta promoter activity in HCV-infected cells is fully restored by the nonstructural protein 3 (NS3) protease inhibitor BILN2061. In contrast, synthetic dsRNA-induced IFN-beta promoter activity is not restored by BILN2061, although it is partially restored by overexpression of RIG-I. These results support recently reported evidence that the HCV NS3 protease blunts the ability of HCV to induce IFN- promoter activity by proteolytically cleaving MAVS/IPS-1. The results also suggest that HCV blocks the synthetic dsRNA-induced signaling pathway at a point upstream of MAVS/IPS-1, and that it does so by an NS3-independent mechanism.
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