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Chronic infection with the hepatitis B virus (HBV) is a major public health problem
and is responsible for 1.2 million deaths per year worldwide. Chronic carriers of
HBV are at high risk of developing chronic hepatitis, liver cirrhosis, and
hepatocellular carcinoma (primary cancer of the liver). Although safe and effective
prophylactic vaccines against HBV are available, antiviral drugs and/or
immunotherapeutics to treat chronically infected human patients are limited.
The woodchuck hepatitis virus (WHV) and its natural host, the Eastern woodchuck
(Marmota monax), is a well-characterized mammalian model available for basic and
therapeutic research on HBV. The woodchuck model has been useful in studies of
the pathogenesis of acute, self-limited and chronic HBV infection, and in the
pre-clinical evaluation of efficacy and, importantly, safety of drug candidates for
treatment of chronic HBV infection and for prevention of hepatocellular carcinoma.
The research in my laboratory is focusing on the innate and adaptive cell-mediated
immunity against WHV in woodchucks. For this purpose an in vitro assay for
quantifying the responses of woodchuck peripheral blood mononuclear cells
(PBMC) to stimulation with viral antigens and peptides was developed. In addition,
a real-time PCR-based assay for quantifying the expression of important antiviral
cytokines such as interferon-gamma and tumor necrosis factor alpha in PBMC
cultures or in lymphocytes within the liver was developed recently. Responses of
PBMC and Th1-/Th2-type cytokine expression profiles of woodchucks chronically
infected with WHV are being investigated in several research settings:
1) In the evaluation of third generation nucleoside analogs as antiviral drugs,
2) In the development or testing of novel immunomodulators for immunotherapy,
3) In the evaluation of new vaccine adjuvants for prophylactic and therapeutic
vaccination, and
4) In studies of WHV pathogenesis in neonatal and adult woodchucks.
The overall goal is to develop new or improved strategies for the treatment of
chronic HBV infection by determining the role of cell-mediated immunity leading to
viral clearance and cure of chronic infection.
Scott D. Butler, Research Support Specialist I
Andrea L. George, Technician III
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