Overview The Hepatitis B and C viruses pose a major health risk and
together comprise two of the world's most challenging virus infections. Their severity lies in the fact that many individuals who are infected are unable to clear the virus successfully, and remain
chronically infected for life. Such infections result in progressive liver damage which may eventually lead to cirrhosis and/or liver cancer. The major goal of the Hepatitis and Liver Unit is to increase our
understanding of the immunopathological mechanisms by which viral hepatitis produces liver disease and how this knowledge can be used to treat patients. 
Specific Projects 1. Studies on the Immunopathology of Hepatitis B
One of our goals in studying the immunology of hepatitis B (HBV) is to understand the relationship between the host's immune response to virus growth during a chronic infection, and its consequences for
damage to the liver. By measuring the amount of killing of virus-infected target cells over time, we have been able to show that
the frequency of cytotoxic T lymphocytes circulating in the blood of chronically infected patients increases during disease episodes. However, because the number of HBV-specific immune cells
circulating in the blood is relatively small, it is technically difficult to measure their function accurately based on cytotoxicity alone. We are currently using more sensitive techniques to refine this analysis
and delineate more precisely which subset of cells are involved with immune attack. We are also studying the clonal composition of the T lymphocytes infiltrating the liver of chronic carriers in order to
understand the degree of specificity involved with such immunopathological responses.
2. Studies of Hepatitis B Virus Expression in Non-Hepatic Cells One of the persisting conundrums relating to HBV is whether cells
outside of the liver are capable of supporting virus replication. By introducing the regulatory elements of the various HBV genes into cells of different lineages such as bone marrow-derived cells,
peripheral blood lymphocytes, and kidney epithelial cells, we have been investigating the ability of these cells to provide the necessary factors for efficient virus gene expression. Our studies indicate that
while expression from the HBV envelope and nucleocapsid promoters are relatively active in these non-hepatic cells, expression from the large surface promoter is largely inactive. This
suggests that HBV may infect non-hepatic cells but is incapable of expressing its full complement of genes, and is therefore unable to produce infectious progeny in these cells. We are currently
investigating whether this limitation can be overcome by treating the cells with cytokines. 3. Modulation of Immune Responses to HBV In collaboration with several national and international centres, we
have been evaluating the efficacy of novel therapeutic drugs for the treatment of chronic hepatitis B and C. We are also developing a number of strategies for boosting the normally indolent immune
responses to HBV seen patients who are chronically infected. One of these involves the use of autologous dendritic cells to present antigen more effectively to patient's own immune cells, whereby it is
hoped that this will result in more effective immune clearance. 4. Hepatitis B Serology Surveillance Study in South Pacific Islanders
Although the HBV vaccine has afforded protection to the great majority of recipients for over 15 years, a small proportion of subjects remain unresponsive to the vaccine and it is still not clear
to what degree these individuals are susceptible to infection by the virus. In collaboration with Dr Bill Carman in London and Dr Locarnini's group in Melbourne, we have been conducting a
multicentre study to assess the efficacy of the vaccine administered to various island communities in the South Pacific. 5. Phylogenetic Analysis of Australan Aboriginal HBV Strains
and their Relationship With Other Published Sequences Viruses evolve in parallel with the host. Because of the remoteness of the Australian continent and its size, viruses of the indigenous
communities in Australia has followed a unique path of development compared to their ancestral origins in South-East Asia and spread subsequently across the Pacific Islands. In collaboration with Dr
Mizokami of Nagoya University, we have been involved in the collection of HBV strains associated with remote Aboriginal communities to see the degree of divergence with those strains
present in the different populations in Asia. Publications
1. Sing GK, Ladhams A, Arnold S, Parmar H, Chen X, Cooper J, Butterworth LA, Stuart K, D'Arcy D and Cooksley WGE. A
longitudinal analysis of cytotoxic T lymphocyte precursor frequencies to the hepatitis B virus in chronically infected patients. J. Viral Hepatitis 8:19-29, 2001.
2. Sing GK, Li D, Chen X, Macnaughton T, Lichanska AM, Butterworth L, Ladhams A, Cooksley G. A molecular comparison of T lymphocyte populations infiltrating the liver and circulating in the
blood of patients with chronic hepatitis B: Evidence for antigen-driven selection of a public complementarity-determining region 3 (CDR3) motif. Hepatology in press
3. Basuni AA, Butterworth L, Cooksley WGE, Locarnini S, Carman WF. An efficient extraction method from blood clots for studies requiring both host and viral DNA. J. Viral Hepatitis 7:241-243,
2000. 4. Schalm SW, Heathcote J, Cianciara J, Farrell G, Sherman M,
Willems B, Dhillon A, Moorat A, Barber J, Gray DF, International Lamivudine Study Group. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection:
a randomised trial. Gut 46:562-568, 2000. 5.
Carreno V, Zeuzem S, Hopf U, Marcellin P, Cooksley WGE, Fevery J, Diago M, Reddy R, Rittweger K, Rakhit A and Pardo M.
A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B. J of Hepatology 32: 317-324, 2000. 6. Cooksley WGE (2000). What did we learn from the Shanghai hepatitis A epidemic? J. Viral Hepatitis
, 7(Suppl 1), 1-3.7. Chan VF, Kunasol P, Cooksley WGE, Isahak I, John J, Loleka S,
Villar EP, Poovorawan Y, Seong NH and Seong NH (2000). Adult immunisation – a neglected issue in Southeast Asia. The Southeast Asian Journal of Trop Medicine and Public Health (in press).
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