Hepatitis C virus often comes to stay for a lifetime

Hepatitis C is a stealthy foe, a moving target to our immune system that can persist in some people for 20 years before it causes chronic liver disease. Ironically, the virus persists virtually by mistake.

David Gretch

As hepatitis C virus (HCV) replicates, it makes what would be considered errors in other systems !M! offspring that are slightly different genetically. Some of these mutant progeny evade our immune defenses more efficiently than others. Ultimately, as the virus continues to replicate, a dominant HCV arises that the body cannot eradicate.

“It is very unusual for a virus to replicate and continue to cause disease in the face of a strong immune response,” explains Dr. David Gretch, associate professor of laboratory medicine and medicine.

HCV leads to persistent infection in 85 percent of the individuals it infects. It is the leading cause of chronic liver disease in the world. In the United States, it is estimated that 4 million people are infected.

Recently, Gretch and his colleagues have made major advances in understanding HCV that will allow them to develop new strategies to fight it.

Last year, Gretch and colleagues published research that shows they can accurately measure the amount of the hepatitis C virus in the blood of infected individuals in chronic stages of liver disease. The research, published in Science, shows that one trillion viruses are produced every day in the livers of patients who have been infected for an average of 15 years.

The half-life of these viral particles in the blood, however, is approximately 2.5 hours. In other words, our system rapidly eliminates HCV virions, but the sheer amount overwhelms the liver, destroying healthy cells.

“We had thought it was a slow replication of the virus and persistence over a long time that caused liver disease,” Gretch said.

Investigators now hope to detect the virus early, before the virus spreads throughout the liver, and deliver drugs that fight the virus and boost the immune system.

A clinical method to detect replicating HCV in fact may be close at hand. Gretch and Dr. Nelson Fausto, professor and chair of the Department of Pathology, are preparing to publish research that shows for the first time that it is possible to detect HCV replication in living human liver tissue.

The research will hopefully lead to the development of a tool to identify the genetically different offspring of replicating HCV and drugs to kill these cells before they become dominant.

Another basic science breakthrough that may have immediate results for patients is the discovery of the specific protein of hepatitis C, NS5A, which inactivates our immune response and allows the virus to replicate. Normally, an enzyme called PKR shuts down viral replication by triggering the immune system to attack an invading virus. But HCV releases NS5A, which binds to PKR and inactivates it.

The discovery will make it less difficult for investigators to develop drugs to impede HCV replication because now they have a specific molecule, NS5A, to target.

Gretch’s other colleagues include Drs. Steve Polyak, an acting assistant professor of laboratory medicine, Michael Katze, professor of microbiology, Robert Carithers, professor of medicine. director of hepatology and medical director of the liver transplant program at UWMC, and James Perkins, professor of surgery and chief of transplant surgery at UWMC. The investigators work together on several NIH-funded research projects.

Gretch, a 1990 M.D., Ph.D. graduate of the University of Iowa, is also assistant director of the Division of Virology and director of Specimen Processing and Phlebotomy at UWMC and Harborview Medical Center.

Gretch, director of the Viral Hepatitis Laboratory at UW Medical Center, will discuss his research in a Science in Medicine Lecture, titled “Biology of Hepatitis C Virus Persistence in Humans,” on Thursday, Nov. 24, from noon to 1 p.m. in room T-625 of the Health Science Center.

Will Morton