Discovery could lead to a new animal model for hepatitis C

January 29, 2009

During its career, the potentially fatal hepatitis C virus has banked its success on a rather unusual strategy: its limitations. Its inability to infect animals other than humans and chimpanzees has severely hampered scientists in developing a useful small animal model for the disease. But now, in a breakthrough to be published in the January 29 advance online issue of Nature, Rockefeller University scientists have identified a protein that allows the virus to enter mouse cells, a finding that represents the clearest path yet for developing a much-needed vaccine as well as tailored treatments for the 170 million people across the globe living with the tenacious, insidious and rapidly changing virus.

By using a genetic screen, the group, led by Charles M. Rice, head of the Laboratory of Virology and Infectious Disease, identified a human protein, called occludin, that makes mouse cells susceptible to the virus. The discovery means that scientists now have the complete list of cellular factors - a total of four - that are required for the virus to enter nonhuman cells.

The hepatitis C virus exclusively targets human liver cells, suggesting that these cells express genes that allow uptake of the virus, genes that are not expressed in other human and nonhuman cells, explains Rice. In past years, three proteins - CD81, CLDN1 and SR-BI - were identified as having key roles in shuttling the virus into cells, but something was clearly missing. Rice's group found that even when they engineered mouse cells to overexpress all three proteins, the cells still denied the virus entry.

The discovery of occludin, however, has changed that. When Rice and his colleagues engineered mouse and human cell lines to express all four proteins, they showed that each cell line became infectible with the virus. To further establish occludin's role as a required entry factor, the group showed that human liver cells naturally express high levels of occludin, and that by silencing its expression, they could give these once highly susceptible liver cells the ability to completely block infection.

"You know, you sort of have to get lucky," says Rice, who is also Maurice R. and Corinne P. Greenberg Professor at Rockefeller. "You've got these three factors you know are important, but you could have 10 other human factors that could have been necessary for hepatitis C virus entry. This work shows that's not the case."

In their DNA screen, the team, including Alexander Ploss, a research associate in the lab, and Matthew J. Evans, currently at Mount Sinai School of Medicine in New York, first cloned all the genes that were expressed in liver cells and then delivered them to mouse cells. "Then, going through an iterative screening process, we honed in on the genes that made the mouse cells permissive," says Ploss, who spearheaded the project with Evans.

Since mice and humans each have a species-specific version of the four factors, the group used hamster cells to see which combination of factors did the best job at making the cells infectible. They found that in the case of two of the proteins, occludin and CD81, only the human versions worked; for SR-BI and CLDN1, the human and mouse versions did an equally good job. These experiments not only suggest that there may be more than one potential animal model, but also that there are several specific combinations of entry factors that could generate them.

"This work provides a clear foundation upon which we can now begin to construct an animal model for the uniquely human pathogen," says Rice. "This is only a first step but in terms of creating an animal model for hepatitis C, it's a big leap forward."

The Rockefeller University

---

---

	Dr. Melissa Palmer's Guide To Hepatitis and Liver Disease by Melissa Palmer (Author) In the United States alone, more than four million people are infected with the hepatitis C virus, and chronic liver disease is the twelfth leading cause of death. In this revised and updated edition of her groundbreaking 2000 book, renowned hepatologist Dr. Melissa Palmer discusses all facets of liver disease, from symptoms and tests to treatment options and lifestyle changes. In addition, this comprehensive handbook reveals cutting-edge research on the dangers of hepatitis C, one of the world's fasting-growing microbial threats.
	The Liver Disorders and Hepatitis Sourcebook (Sourcebooks) by Howard Worman (Author) The latest information on living with and treating liver disorders The Liver Disorders and Hepatitis Sourcebook, Revised Edition, gives you frank assessments of the latest therapies and drugs. It also provides advice on how you can navigate the day-to-day challenges of living with a liver disorder, and diet and nutrition guidelines, including the truth about the effectiveness of herbal remedies and liver-cleansing diets.
	Free from Hepatitis C: Your Complete Guide to Healing Hepatitis C by Lucinda K. Porter (Author) For decades, a diagnosis of hepatitis C was the equivalent of serving a life sentence--with a dangerous liver disease. It left patients frightened, confused, and vulnerable, and they took little comfort in knowing that, at best, their condition could be managed but not cured. All of that changed with the discovery that the hepatitis C virus (HCV) could be defeated with new treatments. To shed light on these groundbreaking treatments, Lucinda Porter, a registered nurse, a passionate HCV advocate, and a Hep C patient herself, has written this all-important guide. This comprehensive volume is a must for anyone considering, undergoing, or just wanting to understand HCV treatment.
	Conquering Hepatitis C And Surviving Treatment: An Essential Guide Through Every Step of The HCV Treatment Process - Companion Website: www.hcvshare.org by Tim Duncan (Author), Catherine Olivolo (Author) Conquering Hepatitis C and Surviving Treatment This book's whole focus is on killing the virus and making it through the necessary treatment journey. Both authors have followed this path. They reveal the latest in research findings on methods to improve treatment success and how to integrate those crucial results in the HCV treatment process. Nine others share their emotional response to learning of their infection, their decision to begin treatment, experiences while undergoing treatment, and what they are doing now. This book provides the necessary information and tools to follow in their footsteps with confidence. - Gives predictive pre-treatment indicators to success. - Shows steps to take to improve chances of success. - Provides proven methods for side effect management. - Reveals...
	Living with Hepatitis C, Fifth Edition: A Survivor's Guide by Gregory T. Everson (Author) The Most Trusted Resource and Reference for Millions of Americans Living with Hepatitis C was the first book to explain in everyday language the causes of this disease, its major and minor symptoms, and all of the latest treatments available. Researchers have continued to make dramatic strides in helping the millions of Americans who suffer from Hepatitis C since the book's first publication, and each new edition has kept up with the most recent findings. The latest revised Living With Hepatitis C, Fifth Edition includes cutting-edge information on: * New treatments including pegylated and consensus interferons * Living-donor transplants * Co-infections with Hepatitis B and HIV/AIDS * Promising new clinical trials of protease and polymerase inhibitors *...
	Living With Hepatitis C For Dummies by Nina L. Paul (Author), Gina Pollichino (Foreword) A comprehensive, empathetic guide for anyone suffering from this serious liver disease Approximately 4 million Americans and 170 million people worldwide suffer from hepatitis C, a viral liver disease that is treatable but not curable. It accounts for more than 40 percent of U.S. liver disease deaths-about 8,000 to 10,000 people annually-and is the most common reason for liver transplantation. This compassionate guide explains how hepatitis C affects the liver and the body and provides solid advice on today's treatment options-from drugs (and their side effects) to transplants and alternative therapies-as well as tips on dealing with the emotional and financial burdens the disease brings with it. Nina L Paul, PhD (New York, NY) earned her doctorate in infectious disease epidemiology...
	The Hepatitis C Handbook by Matthew Dolan (Author), Iain Murray-Lyon (Editor), John Tindall (Editor) This definitive guide explains clearly what Hepatitis C is, outlines the course of the disease and the associated symptoms, and describes how it is transmitted. The author discusses available treatments as well as lifestyle changes that may help. Extensive sections on herbs, vitamins, and nutritional supplements are also included.
	The Hepatitis C Cookbook: Easy and Delicious Recipes by Heather Jeanne (Author), Eugene Sommer (Introduction), Kev Krueger (Introduction) Hepatitis C is a potentially fatal virus that attacks the liver. According to the Centers for Disease Control, Hepatitis C has already infected an estimated four to five million Americans, and worldwide it may have infected as many as 200 million. Most experts agree that if the rate of Hepatitis C infection isn't curbed soon, it will eventually kill more people each year than AIDS. However, Hepatitis C is not always fatal, and it can be fought successfully. For many who suffer from the virus, eating properly can delay the end stages leading to cirrhosis of the liver. It also can diminish the uncomfortable symptoms of the disease. The Hepatitis C Cookbook has been prepared with the special dietary needs of people suffering from Hepatitis C in mind. Hepatitis C does not have to make eating...
	Hepatitis (Diseases and Disorders) by Melissa Abramovitz (Editor) The Diseases & Disorders series offers young readers and researchers a means of understanding ailments and their ramifications. Clear, careful explanations offer insight into what these conditions are, what causes them, how people live with them, and the latest information about treatment and prevention. All volumes include primary and secondary source quotations, annotated bibliographies and lists of organizations to contact for additional information.
	Herbs for Hepatitis C and the Liver (A Storey Medicinal Herb Guide) by Stephen Harrod Buhner (Author) An insightful overview of the impending Hepatitis C epidemic, its causes, the most recent research, and an in-depth, detailed look at the botanical medicines that show promising results for restoring liver function. Includes formulas for using herbs to strengthen the liver and combat disease.