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Immune Therapies For Chronic Hepatitis B Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$359,085.00
Summary
Hepatitis B virus (HBV) causes acute and chronic infection leading to severe liver damage in many patients and increased risk of primary liver cancer. Worldwide ~350 million people have chronic HBV infection and, while a HBV vaccine is available that protects against new infections, current antiviral drug treatments for existing infection are largely ineffective. Thus, the aim of our project is to develop new treatments for chronic HBV infection using vaccination approaches. These therapies will ....Hepatitis B virus (HBV) causes acute and chronic infection leading to severe liver damage in many patients and increased risk of primary liver cancer. Worldwide ~350 million people have chronic HBV infection and, while a HBV vaccine is available that protects against new infections, current antiviral drug treatments for existing infection are largely ineffective. Thus, the aim of our project is to develop new treatments for chronic HBV infection using vaccination approaches. These therapies will be tested in ducks infected with the duck hepatitis B virus (DHBV), a model for human HBV infection. In brief, DHBV-infected ducks will be treated with a new antiviral drug, Entecavir (ETV) developed by Bristol-Myers Squibb, which blocks virus replication. To accelerate clearance of infected cells before drug-resistant viruses can emerge, the ducks will also be treated in combination with different novel therapeutic vaccines designed to induce strong humoral and cell mediated immune responses. Based on outcomes in initial experiments, we will adjust the vaccination protocol in ETV-treated ducks to maximize reductions in the levels of DHBV in liver and bloodstream, rates of death and clearance of DHBV-infected hepatocytes. Our ultimate goal is to define a protocol for combination antiviral and vaccination treatments that allows elimination of HBV infection, or that achieves a level of control of infection that eliminates ongoing disease by reducing virus loads to virtually undetectable levels.Read moreRead less
Clonal Proliferation Of Hepatocytes And Progression Of Liver Disease In Chronic Hepatitis B Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$420,558.00
Summary
Infection with the hepatitis B virus (HBV) can lead to either acute resolving, or chronic HBV infection. Chronic HBV infections are often associated with severe liver disease, and increased risk of liver cancer and occur worldwide in 350 million people. HBV infects hepatocytes, the major cell of the liver. Early during infection 100% of hepatocytes are infected. However, this percentage declines over time to 10-50% or less. The reasons for this are unknown. We suggest that changes in the liver c ....Infection with the hepatitis B virus (HBV) can lead to either acute resolving, or chronic HBV infection. Chronic HBV infections are often associated with severe liver disease, and increased risk of liver cancer and occur worldwide in 350 million people. HBV infects hepatocytes, the major cell of the liver. Early during infection 100% of hepatocytes are infected. However, this percentage declines over time to 10-50% or less. The reasons for this are unknown. We suggest that changes in the liver cell population occur because of the immune response against infected hepatocytes. We hypothesize that the immune response kills infected hepatocytes and provides and growth advantage to hepatocytes that can no longer be infected with HBV. This leads to the clonal proliferation of HBV-negative hepatocytes that over time become the major cell population in the liver. We will study human liver tissue using molecular techniques to detect the HBV DNA that integrates randomly into cell DNA during HBV infection. We will then determine the copy number of specific integrated virus-cell junctions as a measure of hepatocyte proliferation. Sections of fixed liver will also be examined for changes in histology and frequency of HBV infection. These studies will determine if foci of HBV-negative hepatocytes are clonal. This finding would suggest that a major role of the immune system in the development of liver cancer is to restrict the genetic pool of hepatocytes. We hypothesise that liver cancer beings with a very specific survival advantage for hepatocytes that lack HBV replication and antigen expression, and that proliferation of these cells expands the pool of potentially altered HCC precursor cells.Read moreRead less