William S Mason, PhD
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Persistent infection by hepatitis B virus (HBV) leads to chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). Experiments are being carried out to investigate the hypothesis that HCC, and other hepatic lesions associated with chronic HBV infection, initiate with the emergence and clonal expansion of mutated hepatocytes that have lost the ability to support HBV replication. These mutant hepatocytes would have a survival advantage because, unlike normal hepatocytes, they would no longer be targets of the antiviral immune response. This survival advantage would cause them to expand clonally to gradually replace normal hepatocytes.
A possible example of this is shown in the adjacent figure (Figure: Focus of virus free hepatocytes in a woodchuck liver chronically infected with woodchuck hepatitis virus (WHV)). Our studies in woodchucks previously showed that the chronically infected woodchuck liver contains, after a few years, >100,000 clones of greater than 1000 hepatocytes, suggesting a strong selection for clonal expansion of selected hepatocytes after WHV infection. Studies in collaboration with S. Litwin (Fox Chase), R. Lanford (San Antonio) and A. Jilbert (Adelaide), indicate a similar size distribution of clones in chronically infected chimpanzees (Figure: Clonal expansion of hepatocytes in a chimpanzee chronically infected with human HBV), despite a 10-fold or greater duration of infection in the chimpanzees than in the woodchucks. This apparently lower rate of progression of clonal expansion may correlate with the fact that, unlike WHV in woodchucks and HBV in humans, HBV causes a milder liver disease that only rarely progresses to HCC in chimpanzees.
Studies using archived human liver tissue from patients with late stage liver disease, provided in a collaboration with Dr. C. Liu (University of Florida) and Dr. Matthew Yeh (University of Washington), have yielded similar results. Large clones of hepatocytes are found in chronically infected human liver, even in the absence of cirrhosis, which is known to be associated with clonal hepatocyte expansion.
Computer simulations of the liver, in collaboration with Dr. Litwin, indicate that the largest hepatocyte clones found in woodchucks, chimpanzees and humans, could not be created by random death and regeneration of hepatocytes, and must involve selective pressures.
Studies are currently being carried in collaboration with Drs. Patrick Kennedy (London) and Antonio Bertoletti (Singapore) do determine if this extensive clonal expansion is a feature of late stages of human liver disease, or begins in the early stages of infection, up to 30 years of age for those infected at birth, which in many patients is considered to reflect immune tolerance to the virus.Top