Study details hepatitis C ability to block immune system response

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http://www.eurekalert.org/pub_releases/2006-05/sri-sdh051706.php

 

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.

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.

 

 

 

 

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