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A New Insight Into Hepatitis B Infection:the HBV Fusion Peptide
Funder
National Health and Medical Research Council
Funding Amount
$288,210.00
Summary
Three hundred and fifty million people worldwide and 250,000 in Australia are chronically infected with hepatitis B virus (HBV). Without intervention, one third will die as a direct result of this infection through cirrhosis, liver failure and liver cancer, but current therapies are inadequate. New antiviral treatments requiring the identification of new antiviral targets are needed to combat the disease but a major obstacle to the study of HBV is the lack of a cell culture system. As a result n ....Three hundred and fifty million people worldwide and 250,000 in Australia are chronically infected with hepatitis B virus (HBV). Without intervention, one third will die as a direct result of this infection through cirrhosis, liver failure and liver cancer, but current therapies are inadequate. New antiviral treatments requiring the identification of new antiviral targets are needed to combat the disease but a major obstacle to the study of HBV is the lack of a cell culture system. As a result nothing is known about how HBV enter and fuses with the host liver cell but we have made significant progress with the identification of the entry and fusion events of the related duck hepatitis B virus, using the duck infection model. This knowledge is now ready for application to the medically important HBV by use of primary human liver cells and the techniques developed in the duck hepatitis B virus model.Read moreRead less
Chronic Active Viral Persistence Versus Host Immune Mediated Pathology: An Analysis And Manipulation Of The Balance.
Funder
National Health and Medical Research Council
Funding Amount
$418,658.00
Summary
Our robust ability to mount an immune response and clear infections is tempered by the possibility of promoting autoimmunity. Several host genes regulate immunity. Viruses like HIV have exploited these to abrogate antiviral immunity. This project attempts to define host factors that promote chronic infection. This will be extremely valuable in understanding the vulnerabilities of our immune system and provide an insight into how we can treat chronic infections.
Clearing Chronic Infectious Diseases – Enhancing Host Immune Effector Function
Funder
National Health and Medical Research Council
Funding Amount
$92,314.00
Summary
Chronic infections produced by pathogens such as HIV, overwhelm our immune system leading to an exhausted state where cells responsible for the clearance of invading microorganisms are unable to respond effectively. We have recently identified a highly promising therapeutic target that enhances immune effector function. We seek to understand the underlying mechanism, and to explore the therapeutic potential of this approach for the treatment of a broad range of pathogens, including those respons ....Chronic infections produced by pathogens such as HIV, overwhelm our immune system leading to an exhausted state where cells responsible for the clearance of invading microorganisms are unable to respond effectively. We have recently identified a highly promising therapeutic target that enhances immune effector function. We seek to understand the underlying mechanism, and to explore the therapeutic potential of this approach for the treatment of a broad range of pathogens, including those responsible for chronic disease.Read moreRead less
Protein Topogenesis And The Assembly/disassembly Of The Enveloped Hepatitis B Virus.
Funder
National Health and Medical Research Council
Funding Amount
$197,884.00
Summary
An estimated 350 million people worldwide, and 250,000 in Australia, are chronically infected with the hepatitis B virus (HBV). Without intervention, one third will die as a direct result of this infection through cirrhosis, liver failure and liver cancer, but current treatments are inadequate. A major obstacle to the study of this virus is the lack of a cell culture infection system. We have used the duck hepatitis B virus (DHBV) model to study the events leading up to assembly of the virus in ....An estimated 350 million people worldwide, and 250,000 in Australia, are chronically infected with the hepatitis B virus (HBV). Without intervention, one third will die as a direct result of this infection through cirrhosis, liver failure and liver cancer, but current treatments are inadequate. A major obstacle to the study of this virus is the lack of a cell culture infection system. We have used the duck hepatitis B virus (DHBV) model to study the events leading up to assembly of the virus in a way which prepares the viral envelope or outer coat for its foray into a new host cell. The project will examine the specific interactions of two proteins, the large and the small envelope protein, in addition to a third envelope protein we have recently discovered, which together make up the viral envelope. This will reveal which envelope components are required to make up the specific structures known to be essential for the disruption of the host cell membrane and subsequent entry of the virus to a new cell. An understanding of the changes that occur to the viral envelope upon entry will enable development of strategies for the inhibition or blocking of this change, thus identifying targets for the development of new antiviral agents. Because HBV is just one of many viruses which have an envelope, all of which must enter the cell in some way, our studies of HBV will also provide new clues with respect to the replication of other viruses such as measles, influenza and HIV. A related part of the study will examine the orientation of the large envelope protein within the virus particle and how it changes its orientation to assume its many important functional roles, in the late stages of particle assembly. Expanding on our finding that the small protein is essential to the orientation of the large protein, this study will reveal the mechanism of a unique method of protein transport which may have wider implications in cell biology.Read moreRead less
Polarized Epithelia And The Natural History Of Hepatitis Viruses
Funder
National Health and Medical Research Council
Funding Amount
$358,770.00
Summary
The viruses causing hepatitis in man must cross specialised cell layers in the body to reach the liver, and must again cross these cell layers and liver cells in order to be transmitted to subsequent hosts. This research will examine how each of the hepatitis viruses (HAV to HEV) are able to enter and exit the body, and the role that these mechanisms may play in the development of acute disease and of chronic infections with hepatitis B and C viruses. The findings will contribute to development ....The viruses causing hepatitis in man must cross specialised cell layers in the body to reach the liver, and must again cross these cell layers and liver cells in order to be transmitted to subsequent hosts. This research will examine how each of the hepatitis viruses (HAV to HEV) are able to enter and exit the body, and the role that these mechanisms may play in the development of acute disease and of chronic infections with hepatitis B and C viruses. The findings will contribute to development of improved methods for the prevention and control of viral hepatitis.Read moreRead less
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
Characterisation Of Anti-HBs Responses In Patients Undergoing Functional Hepatitis B Cure: Implication For Future Therapies
Funder
National Health and Medical Research Council
Funding Amount
$723,649.00
Summary
The hepatitis B virus causes liver cirrhosis and liver cancer. There is no cure for hepatitis B. However, a small number of patients can naturally rid themselves of the virus. We have identified 14 of these individuals and discovered that they have a unique immune response that is responsible for these “natural” cures. We plan to characterise this immune response and turn it into a therapeutic vaccine which can be used to cure patients who are still chronically infected.
Worldwide >360 million people have chronic hepatitis B virus (HBV) infection that imparts a 25% lifetime risk of death due to serious liver disease. Current therapies for chronic HBV reduce levels of virus replication but fail to target the stable, nuclear episome, covalently closed circular DNA (cccDNA). The current study will determine what is required to eliminate cccDNA and how current therapies for chronic HBV infection should be modified to achieve this aim.
ANTIVIRAL DRUG RESISTANT HBV: PATHOGENIC AND ONCOGENIC SIGNIFICANCE OF THE ALTERED VIRAL ENVELOPE
Funder
National Health and Medical Research Council
Funding Amount
$509,284.00
Summary
We aim to investigate the consequences of long-term therapy for hepatitis B on liver cancer progression. We propose that antiviral therapy is associated with persistent expression and accumulation of potentially oncogenic surface proteins in the liver. This can dramatically alter the viral lifecycle, particularly the HBsAg secretion pathway, which can cause serious effects in the host hepatocyte biology, including promoting pathways to tumour formation.
The Role Of Stellate Cells In Fibrosis And Liver Disease Progression In HIV-Hepatitis B Co-infection
Funder
National Health and Medical Research Council
Funding Amount
$157,292.00
Summary
Liver related mortality is the commonest cause of non-AIDS death in HIV infected individuals on treatment. With HIV, HBV liver damage is accelerated and liver-related mortality increased. Understanding how and why is critical to management. I will examine the role of hepatic stellate cells using in vitro models and directly ex vivo from infected patient biopsy tissue. I will investigate the activated of these cells by HIV and HBV infection, thus promoting scar formation with liver injury.