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CC’s Stored Blood Samples Crucial to Findings
Researchers from the Clinical Center, NIAID, and other institutions have discovered a clue to the mystery of why up to 85 percent of patients fail to recover fully from an infection with the hepatitis C virus (HCV). HCV is a major cause of chronic liver disease, cirrhosis, and liver cell cancer. Their research, reported in the April 14 issue of “Science,” points to changes in surface proteins that enable the virus to escape the immune system. The study shows that the destiny of an HCV infection is determined during the initial, acute phase of disease.
“We know that the hepatitis C virus can simultaneously exist as a family of closely related but immunologically distinct variants that has been termed ‘quasispecies, said senior author Dr. Harvey Alter, chief of the Infectious Diseases Section of the CC’s Department of Transfusion Medicine. “We have patients who have 20-30 different hepatitis C viruses in their serum at one time. The question was whether this ability of the virus to exist in these different forms could be a mechanism to escape the host’s immune response.”
In a search for the answer, Dr. Alter offered a unique resource: a storehouse of blood samples amassed from his long-term studies of patients who contracted hepatitis from blood transfusions. The samples provided a continual record of what the virus was doing in each patient’s bloodstream over, in some cases, 20 years.
“This unique group was critical for our study, because they had been observed continuously since early in infection,” stated lead author Dr. Patrizia Farci.
Samples were selected from the first 4 months of infection in twelve patients with different clinical outcomes: acute HCV infection, fulminant hepatitis (a rare but serious form of acute disease), or chronic hepatitis. The research team examined serum samples taken at different time points in each patient, 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 immune response was sufficient to neutralize the virus and decrease the variants, presumably one by one, until the infection was eradicated and clinical recovery ensued. But in other patients the immune response was insufficient to clear the virus, and instead served to drive a system wherein the virus kept escaping the immune attack by becoming more and more diverse. These patients developed chronic liver disease,” said Dr. Alter.
Similar mechanisms are used by other viruses, such as HIV and influenza, but this is the first study to correlate such behavior with dis- ease progression in hepatitis C. The researchers also determined a region in the virus surface protein (envelope) where most of the changes occur.
Studies will now focus on the types of mutations that assist HCVin avoiding the immune system, and on the types of antibodies produced during the early response.
“Once we understand the host-virus interrelationships, we might be able to do things to alter that relationship. Particularly, we might be able to combine a strategy that would suppress viral replication with one that would stimulate the immune response,” Dr. Alter said.
Dr. Alter’ s valued blood samples have been used in numerous studies, and they are running low.
“We’ve already run out of some of these samples. They are irreplaceable, unfortunately. We are a victim of our own success because we now have such good screening measures that we no longer see any cases of transfusion-associated hepatitis C. We are setting up a new prospective study to look at other viruses, in addition to primary hepatitis viruses, and to establish a comprehensive donor recipient repository so that if a new virus is discovered, we could immediately plug into the samples and prove whether it is transfusion-transmitted and hence a threat to the blood supply,” Dr. Alter said.
Other collaborators from NIH, University of Cagliari, Kanazawa University (Japan), Chiron Corporation, and Albert Einstein Medical Center participated in this study.