Scientists from the National Institutes of Health (NIH) and other institutions have discovered a clue that begins to explain why so many patients fail to fully recover from infection with the hepatitis C virus (HCV). Their research, reported in the current issue of Science, points to changes in surface proteins that enable the virus to evade the immune system. The study shows that the ultimate outcome of an HCV infection is determined during the initial, acute phase of disease.

"Hepatitis C is a devastating disease that exacts a significant toll in this country and abroad, and whose full clinical impact has yet to be realized," states Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID) at the NIH. "This research helps to explain how the virus manages to persist in the body and provides physicians with a potential way to predict the development of a chronic infection."

Nearly 4 million Americans have been infected with the hepatitis C virus (HCV). Of those who contract hepatitis C, 85 percent remain chronically infected, harboring a virus that continues to replicate throughout a person's life. HCV is a major cause of chronic liver disease and is responsible for a third of all cases of cirrhosis and liver cancer, half of all liver transplants, and 8,000 to 10,000 deaths in this country annually.

Patrizia Farci, M.D., and Robert Purcell, M.D., of NIAID and Harvey Alter, M.D., of the NIH Warren Magnuson Clinical Center, led a team of scientists in a study designed to see whether the hepatitis C virus changes during infection. Dr. Alter had been conducting long-term studies of patients who contracted hepatitis from blood transfusions. These individuals subsequently developed different clinical outcomes, ranging from short-term infections to chronic disease. Some of these patients have had hepatitis C for over 20 years. "This unique group was critical for our study, because they had been observed continuously since early in infection," states Dr. Farci, who splits her time between NIAID in the United States and the University of Cagliari in Italy.

Three of the 12 patients studied had acute HCV infections, three had fulminant hepatitis (a rare but serious form of acute disease), and six had chronic hepatitis. The research team examined the virus in each person, looking specifically for changes in the genes that encode special proteins coating the viral surface. They also studied what changes occurred either before or after the body's immune system responded to HCV infection.

In some patients, the virus remained relatively unchanged following the initial immune response, and those people completely eliminated HCV over several weeks. In most, however, genetic HCV variants began to appear in response to the early immune assault. This rapid viral evolution ultimately resulted in chronic infection.

"We know that the body responds to infection early in the disease process, but in most patients the virus is 'smarter' than the immune system," states Dr. Farci. "In many cases, HCV changes its surface proteins as soon as the patient's antibodies begin to attack. In essence, the virus slips into a disguise and continues on without detection."

Similar masquerades are used by other viruses, such as HIV and influenza, but this is the first study to correlate such behavior with disease progression in hepatitis C. The researchers also determined a region on virus surface proteins where most of the changes occur. Their studies will now focus on the types of mutations that assist HCV in avoiding the immune system, and on the types of antibodies produced during the early response. By understanding more about this critical checkpoint in HCV infection, they hope to develop new tools for hepatitis C treatment and prevention.