Researchers at the University of Washington report in the April 14, 1997 issue of Virology that they may have an explanation for why the currently approved drug treatment for hepatitis C is ineffective much of the time. The drug, recombinant alpha interferon, is ineffective in 60 to 80 percent of cases.
"This discovery explains the molecular mechanisms for interferon resistance, and points the way to a potential new target for therapeutic drugs to treat hepatitis C," said the principal investigator, Dr. Michael G. Katze (kates), UW professor of microbiology and associate director of the UW's Regional Primate Research Center.
The UW's Office of Technology Transfer has negotiated a patent-based licensing agreement with RiboGene, Inc., a privately-held biotechnology company in Hayward, Calif., which will begin investigating drug therapies based on the UW discovery. Katze is a member of the company's scientific advisory board.
Hepatitis C (formerly called non-A, non-B hepatitis), caused by the virus, affects more than 3.5 million Americans. It is the major reason for liver failure necessitating liver transplants.
"Many viruses that affect humans -- hepatitis, influenza, herpes, HIV, polio and a host of others -- have evolved mechanisms to resist the effects of interferon, one of the body's first lines of defense against viruses," said Dr. Michael Gale, Jr., UW microbiology fellow who is lead scientist and first author of the study. The drug interferon is an artificial version of naturally-occurring interferon, a protein secreted by cells that "interferes with" viral infection and other challenges.
Earlier studies in Japan showed that interferon-resistant HCV strains have a specific RNA sequence within a region of the virus called NS5A. The UW researchers followed up on this research, and tested the ability of NS5A to interact with a key component of interferon response called PKR, a member of an important family of enzymes called protein kinases.
Katze and his team found that the NS5A protein in two strains of HCV -- one found mainly in the United States, the other in Asia -- had the ability to bind to and inactivate PKR. "This has strong implications," said Gale. "We have shown that PKR is important in the interferon response."
"We believe we've identified a potential target for therapeutics," said Katze. "If a compound can be identified that inhibits or prevents the association of NS5A with PKR without affecting PKR's ability to function, interferon response could be restored. If the compound were administered in combination with interferon, it could potentially bring the virus under control and allow the body's immune system to knock it out." Katze cautions that while his team's research is an important first step, a therapy for HCV is not around the corner.
The study is published in the April 14 edition of Virology (vol. 230, no. 2, pp. 217-227, Academic Press) and funded by the National Institutes of Health. Co-authors are Drs. Marcus J. Korth, Norina M. Tang, Seng-Lai Tan, Deborah A. Hopkins, Stephen J. Polyak and David R. Gretch, all of the University of Washington; and Thomas E. Dever of the National Institute of Child Health and Human Development.
Facts About Hepatitis C
Up to 3.5 million Americans are believed chronically infected with the hepatitis C virus, formerly called non-A, non-B hepatitis. Some 20 to 40 percent of people coming to inner-city hospitals have the virus, as do about 80 percent of intravenous drug users. While hepatitis C is transmitted through blood and shared needles, studies have shown that about 40 percent of carriers do not report such risk factors. The nation's blood supply has been tested for hepatitis C since 1990.
The disease causes symptoms such as fatigue, nausea, loss of appetite, dark urine and jaundice, but up to 70 percent of patients lack symptoms in the early stages. Infected individuals usually are unaware of their disease until they develop serious complications. The disease may occur in the acute form and be followed by recovery, or it may become chronic and cause symptoms for years.
The federal Centers for Disease Control and Prevention (CDC) estimates that 20 to 50 percent of chronically infected hepatitis C patients will develop cirrhosis of the liver, and 20 to 30 percent of those will develop liver cancer or liver failure requiring transplant.
There are an estimated 150,000 to 250,000 new cases of hepatitis C infection each year in the U.S., and the disease contributes to the death of more than 12,000 American annually; this toll is expected to triple by the year 2010, according to the CDC.