Imaging The Hepatitis C Virus Life Cycle In Real-time
Funder
National Health and Medical Research Council
Funding Amount
$477,504.00
Summary
Hepatitis C virus (HCV) is a serious viral pathogen that causes significant liver disease. This proposal plans to examine how two proteins from the HCV, core and NS5A, interact with host proteins and pathways to facilitate viral replication and release of HCV; two processes that are poorly understood. Specifically we will tag viral proteins to allow us to investigate the HCV life cycle in living cells and determine the role of core and NS5A in facilitating HCV replication. This proposal may unco ....Hepatitis C virus (HCV) is a serious viral pathogen that causes significant liver disease. This proposal plans to examine how two proteins from the HCV, core and NS5A, interact with host proteins and pathways to facilitate viral replication and release of HCV; two processes that are poorly understood. Specifically we will tag viral proteins to allow us to investigate the HCV life cycle in living cells and determine the role of core and NS5A in facilitating HCV replication. This proposal may uncover novel therapeutic strategies to combat HCV.Read moreRead less
Induction Of Reactive Oxygen Species By Hepatitis C Virus And Its Role In Liver Pathogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$376,320.00
Summary
The majority of individuals infected with hepatitis C virus (HCV) show a slow progression of liver disease over a period of 20-30 years. There is increased scaring of the liver which can result in liver failure and in some individuals liver cancer. Due to the lack of suitable model systems to study HCV infection and disease progression there is no currently available vaccine and treatment options are limited. While the host defense mechanisms to HCV are relatively well studied the role that vira ....The majority of individuals infected with hepatitis C virus (HCV) show a slow progression of liver disease over a period of 20-30 years. There is increased scaring of the liver which can result in liver failure and in some individuals liver cancer. Due to the lack of suitable model systems to study HCV infection and disease progression there is no currently available vaccine and treatment options are limited. While the host defense mechanisms to HCV are relatively well studied the role that viral proteins and viral replication play in the development of liver disease are not well characterized. Previous experiments in the laboratory have shown that one of the hepatitis C virus proteins results in the formation of toxic oxygen molecules known as a reactive oxygen species. This toxic oxygen molecules can have an effect on liver cells that may enhance the progression of the liver disease process in hepatitis C virus infected individuals. The role that these molecules play in liver cells is unknown but experiments are planned in laboratory model systems and in specimens obtained from hepatitis C virus infected individuals to further examine potential mechanisms. This will hopefully lead to the identification of new treatments for hepatitis C virus liver disease. Some patients with hepatitis C will develop liver cancer, however, all the reasons are not known. Using new technology known as microarray, a consequence of the human genome project, we have been able to look at the expression levels of thousands of genes in liver cancer. Experiments are planned to determine if these genes are important in liver cancer and if they can be used as targets for therapy or to more easily diagnose liver cancer.Read moreRead less
Novel Bioinformatic Methods To Determine The Link Between Genomic Complexity Of Hepatitis Viruses And Liver Disease Phenotypes
Funder
National Health and Medical Research Council
Funding Amount
$605,859.00
Summary
Bioinformatics is a discipline concerned with the study of how information is stored and used in biological systems. Here we develop bioinformatic tools to study how hepatitis viruses evolve during an infection and how these infections cause severe liver diseases.
Host Determinants Of Hepatitis C-associated Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$610,376.00
Summary
Hepatitis C virus (HCV) infection is a major cause of liver disease and associated deaths in Australia. HCV infection leads to progressive liver failure and may be associated with the development of liver cancer. Currently there are an estimated 220,000 people in Australia living with HCV infection, and by 2020 it is estimated that this number will treble. There is now considerable evidence to indicate that the effect of HCV on the liver is due to ongoing immune activity and the build up of fat ....Hepatitis C virus (HCV) infection is a major cause of liver disease and associated deaths in Australia. HCV infection leads to progressive liver failure and may be associated with the development of liver cancer. Currently there are an estimated 220,000 people in Australia living with HCV infection, and by 2020 it is estimated that this number will treble. There is now considerable evidence to indicate that the effect of HCV on the liver is due to ongoing immune activity and the build up of fat (steatosis) in the liver. This results in the production of biochemical products that lead to tissue damage and to eventual destruction of the liver. Further evidence has recently emerged to suggest that the susceptibility to, and outcome of HCV infection may be influenced by genetic variation in the infected population. The chief investigators on this project have established the best characterised clinical cohort of HCV infected persons worldwide. Further, they have developed considerable expertise in the field of genetics, i.e. the analysis of genes that influence the host's response to an illness. Using this information and expertise, we propose in the present study to analyse in detail the host genetic factors that contribute to variations in the response to HCV, and its correlation with HCV-associated liver damage. This data could allow the development of better patient care strategies and the design of novel therapeutics.Read moreRead less
The Effect Of Exercise On Insulin Resistance And The Adipokine Profile In Obese Versus Non Obese Patients With Hepatitis C
Funder
National Health and Medical Research Council
Funding Amount
$100,381.00
Summary
Chronic hepatitis C (CHC) infection and obesity are conditions of increasing prevalence. Untreated, CHC has significant long-term consequences including cirrhosis and liver failure, while obesity reduces the success of antiviral treatment. A tendency to develop diabetes in patients with CHC and obesity also leads to further medical complications. We aim to examine the effects of exercise on obesity and diabetes tendency in patients with CHC.
Profiling The Specificity Of The Neutralizing Antibody Response In People Who Have Long Term Protection From Developing Chronic HCV
Funder
National Health and Medical Research Council
Funding Amount
$372,972.00
Summary
Hepatitis C causes chronic liver disease in over 150 million people world-wide. In this study we will determine the qualities of the immune response that protect individuals from HCV infection and reinfection. The outcomes of this study will provide a pathway for the development of vaccines that elicit protective immune signatures.
Hepatitis C virus (HCV), the main cause of of post-transfusion and community -acquired non-A, non-B hepatitis, infects approximately 170 million humans world-wide with some 135,000 infections in Australia alone. HCV is hyper-endemic in intravenous blood users with typical prevalence rates of 60-70%. About 75-80% of infected individuals develop a chronic infection, usually resulting in recurrent, progressively worsening liver damage. Cirrhosis develops in 10-20% of chronic cases while 1-5% of chr ....Hepatitis C virus (HCV), the main cause of of post-transfusion and community -acquired non-A, non-B hepatitis, infects approximately 170 million humans world-wide with some 135,000 infections in Australia alone. HCV is hyper-endemic in intravenous blood users with typical prevalence rates of 60-70%. About 75-80% of infected individuals develop a chronic infection, usually resulting in recurrent, progressively worsening liver damage. Cirrhosis develops in 10-20% of chronic cases while 1-5% of chronic carriers develop liver cancer. Development of an effective vaccine is complicated due to the highly variable nature of the virus. Approved therapies include alpha-interferon and alpha interferon-ribavirin combinations but these treatments induce efficacious responses in only 20-30% of patients and often have severe side-effects. It is assumed that after attachment of HCV to the cell surface, the virus is internalised by the cell and undergoes fusion with a cellular compartment referred to as an endosome. The low pH environment of the endosome is presumed to trigger viral fusion via its cell surface glycoproteins and empties the replication machinery of the virus into the cell. No reliable systems for the propagation of HCV are available thereby limiting studies into the mechanisms of how HCV infects cells and the development of vaccines. Recently a cell surface molecule, CD81, was identified as a possible receptor for the attachment of HCV to susceptible cells. Our aim is to 1) develop model systems for studying HCV entry and fusion and 2) further characterise the interaction of the HCV glycoproteins with CD81 with the goal of obtaining a three-dimersional structure of the interaction . These studies will address the fundamental questions of how HCV enters cells leading new avenues for the design of inhibitors of HCV entry.Read moreRead less
The Role Of Obesity, Insulin Resistance And Fatty Liver (steatosis) In Human Disease And Strategies To Monitor And Improve Patient Outcomes
Funder
National Health and Medical Research Council
Funding Amount
$322,892.00
Summary
The overall objective of my research activity is to examine in human subjects, the mechanisms by which obesity and fatty liver impair the response of the liver to injury and inflammation from multiple causes and to develop specific strategies to monitor and improve the outcome of treatment in overweight patients with liver disease.
Novel Approaches To The Pathogenesis Of Chronic Hepatitis C Virus Associated Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
The incidence of hepatitis C virus (HCV) infection is rapidly increasing in our community. This infection cannot be prevented by vaccination and the current treatments often fail. We believe that the novel approaches we are taking towards gaining an improved understanding of this disease process have the potential to lead to better therapies. We propose to examine disease progression using the new technology of gene array which scans thousands of genes simultaneously to find those most activated ....The incidence of hepatitis C virus (HCV) infection is rapidly increasing in our community. This infection cannot be prevented by vaccination and the current treatments often fail. We believe that the novel approaches we are taking towards gaining an improved understanding of this disease process have the potential to lead to better therapies. We propose to examine disease progression using the new technology of gene array which scans thousands of genes simultaneously to find those most activated. Our preliminary experiments indicated that one particular set of genes related to cell death is upregulated in HCV cirrhosis more than in other kinds of cirrhosis. We propose to pursue the diagnostic-prognostic potential of one of these molecules. Primarily this project will ask what kinds of genes are activated by HCV infection and at various stages of disease progression through to fibrosis and cirrhosis and following liver transplantation to better understand these processes. We believe that this research is likely to lead to a new understanding of hepatitis C associated liver disease that may lead to novel approaches to therapy.Read moreRead less