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
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
Structure And Function Of Hepatitis C Virus Glycoproteins
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
Hepatitis C Virus infects approximately 200 million people world-wide and is the major cause of liver transplantation in the Western world. At present there is no vaccine and interferon alpha is the only therapy available and has only limited success in clearing viral infection. HCV is distantly related to flaviviruses eg tick-borne encephaltitis virus and yellow fever virus. All viruses attach to target cells using receptors to initiate the infection process. In the case of HCV, the envelope gl ....Hepatitis C Virus infects approximately 200 million people world-wide and is the major cause of liver transplantation in the Western world. At present there is no vaccine and interferon alpha is the only therapy available and has only limited success in clearing viral infection. HCV is distantly related to flaviviruses eg tick-borne encephaltitis virus and yellow fever virus. All viruses attach to target cells using receptors to initiate the infection process. In the case of HCV, the envelope glycoproteins interact with as yet unknown receptors on the target cell surface resulting in the virus being internalized into endosomes. It is believed that the low pH environment of these endosomes triggers fusion of the viral and cellular membranes. After fusion the genome of the virus is released into target cells and begins the replication process. The actual events intitiating these processes are not understood for HCV but are believed to be mediated using two envelope glycoproteins. In this project we seek to gain a greater understanding of how viral fusion and entry occurs. We have new information regarding the localisation of the two envelope glycoproteins that will now enable us to carefully examine how viral fusion occurs. Using biochemical approaches, we will study their structure and function and examine how this relates to the well understood flavivirus mode of fusion and entry. We will test the functional consequences of altering the structure of the HCV envelope glycoproteins by developing in vitro assays of HCV fusion. Assays for HCV fusion are essential for future studies to identify viral receptors, examine the role of antibody in viral neutralization and can be used to test novel inhibitors of viral fusion and entry.Read moreRead less
Fine Positioning And Effector Function Of T Cells Recruited To The HCV Infected Liver
Funder
National Health and Medical Research Council
Funding Amount
$321,973.00
Summary
The majority of patients who become infected with hepatitis C virus (HCV) are unable to mount an effective immune response and clear the virus and therefore develop lifelong (chronic) infection. The persistence of virus in the liver of patients with chronic infection results in the recruitment of significant numbers of immune cells, notably T cells, from the bloodstream into the liver where they are involved in both viral control (but not viral clearance) and liver injury. The level of tissue in ....The majority of patients who become infected with hepatitis C virus (HCV) are unable to mount an effective immune response and clear the virus and therefore develop lifelong (chronic) infection. The persistence of virus in the liver of patients with chronic infection results in the recruitment of significant numbers of immune cells, notably T cells, from the bloodstream into the liver where they are involved in both viral control (but not viral clearance) and liver injury. The level of tissue injury observed and the speed of disease progression may be linked to the type of T cells recruited, their function, and their position in the liver. The aims of this project are to determine the factors involved in the fine positioning of T cells in the liver and establish a relationship between T cell recruitment, function, and progression of HCV disease in the liver.Read moreRead less
Behavioural, Virological And Immunological Factors Influencing Hepatitis C Virus Infection In Injecting Drug Users
Funder
National Health and Medical Research Council
Funding Amount
$963,437.00
Summary
The hepatitis C virus (HCV) is a major public health problem affecting over 170 million people worldwide. In Australia an estimated 157,000 people have HCV and are at risk of serious disease, and 16,000 new infections occur each year. Treating HCV-related disease is expensive, and this healthcare burden is projected to grow significantly in coming years. Almost all new HCV infections in Australia occur among injecting drug users (IDUs), and despite our world-leading prevention programs, the viru ....The hepatitis C virus (HCV) is a major public health problem affecting over 170 million people worldwide. In Australia an estimated 157,000 people have HCV and are at risk of serious disease, and 16,000 new infections occur each year. Treating HCV-related disease is expensive, and this healthcare burden is projected to grow significantly in coming years. Almost all new HCV infections in Australia occur among injecting drug users (IDUs), and despite our world-leading prevention programs, the virus is spreading. Consensus is emerging that the best hope for control of HCV and related disease lies in a vaccine; our research will lay much of the groundwork for its development. The applicants' research to date shows that IDUs are being infected with HCV more frequently than previously assumed, that many carry multiple strains, and that dominant strains vary rapidly in individuals over time. These results reinforce the view that our prevention methods will not reduce infection rates and that current anti-viral treatments are not the solution. Nevertheless, we also found that some IDUs remain free of HCV infection despite risky behaviour with infected associates; intensive study of the immune functioning of these persistently non-infected individuals holds promise for vaccine development. In our proposed research, a collaboration of leading Australian epidemiologists, virologists and immunologists, we will recruit 210 young IDUs and follow them regularly for two years. Recruits will describe their social networks and nominate IDUs with whom they inject, provide blood samples and be interviewed about their behaviour at 3-month intervals. Individuals with recent and resolved HCV infection, change of dominant strain and lack of infection despite risky behaviour will be identified and their blood analysed for genetic factors that may be linked to immune protection. The outcomes will be crucial to the development and trialling of a vaccine against HCV.Read moreRead less
Defining Risk And Mechanisms Of Permucosal Transmission For Acute HCV Infection Within High-risk Populations.
Funder
National Health and Medical Research Council
Funding Amount
$395,182.00
Summary
Hepatitis C virus (HCV) is usually transmitted by blood-to-blood contact. The risk of transmission by sexual contact has been thought to be low. However, in recent years increasing hepatitis C infection has been documented among HIV-positive gay men, with sexual contact the most most likely means of infection in the majority of cases. This grant will use established cohorts to define levels of hepatitis C risk through sexual contact among homosexual men to inform public health strategies.
Detailed Investigation Of The Humoral Immune Response To HCV To Identify Diagnostic And Prognostic Serological Markers
Funder
National Health and Medical Research Council
Funding Amount
$387,466.00
Summary
The prevalence of Hepatitis C in Australia has been estimated at 242 000 people with 80% of infections acquired as a result of infection drug use. The currently available assays can be used to reliably determine the prevalence of Hepatitis C infection but provide no information regarding the incidence of infection. By thoroughly investigating the immune response generated by individuals infected with Hepatitis C we intend to identify interactions which can be used to differientiate between the d ....The prevalence of Hepatitis C in Australia has been estimated at 242 000 people with 80% of infections acquired as a result of infection drug use. The currently available assays can be used to reliably determine the prevalence of Hepatitis C infection but provide no information regarding the incidence of infection. By thoroughly investigating the immune response generated by individuals infected with Hepatitis C we intend to identify interactions which can be used to differientiate between the different stages of infection. The expected outcomes of this study include the identification of a marker of recent Hepatitis C infection. This will permit accurate epidemiological monitoring of Hepatitis C, better design of programs to control the spread, trace outbreaks and manage treatment programs. The identification of a marker capable of predicting the clinical outcome of infection would be invaluable to clinicians, because following acute infection with Hepatitis C, 20 to 30% of individuals will resolve their infection without the need for therapeutic intervention. The information obtained in this study will also lead to a better interpretation of diagnostic laboratory findings, improving our ability to provide clear and accurate reports to blood donors and consequently enhance the Australian blood supply in terms of safety and donor retention.Read moreRead less
A Virus-like Particle Vaccine For Hepatitis C Virus.
Funder
National Health and Medical Research Council
Funding Amount
$199,013.00
Summary
The aim is to evaluate the efficiency of a virus-like particle (VLP) vaccine for hepatitis C virus (HCV). HCV infects about 10,000 people every year in Australia and approximately 8, 000 of these will develop persistent infection. As a result, there are currently 150,000-200,000 HCV carriers in Australia and 500 million worldwide. These individuals represent a source of infection. Although the major route for transmission is blood and blood products, the advent of HCV screening in the blood bank ....The aim is to evaluate the efficiency of a virus-like particle (VLP) vaccine for hepatitis C virus (HCV). HCV infects about 10,000 people every year in Australia and approximately 8, 000 of these will develop persistent infection. As a result, there are currently 150,000-200,000 HCV carriers in Australia and 500 million worldwide. These individuals represent a source of infection. Although the major route for transmission is blood and blood products, the advent of HCV screening in the blood banks has reduced the risk of infection from this source. However, many intravenous drug users (IVD) share needles and although it is not common, transmission to spouses of carriers is well recognised. In addition, approximately 20% of HCV carriers have no recognised risk factor and it is unclear how these individuals became infected. Transmission of the virus to hospital inpatients and outpatients is also well recognised and as a result, it is clear that a vaccine is urgently required. However, as HCV cannot be cultured in the laboratory, it is impossible to develop a traditional vaccine; furthermore, because a proportion of patients who recover from HCV infection have no specific immunity and thus can be re-infected, the design of a vaccine presents a number of problems. Thus a vaccine which is based on the development of neutralising antibody is unlikely to be effective, in contrast to a vaccine which is designed to generate a cellular immune response. VLPs induce an effective cellular immune response and we plan to make VLPs composed of the L1 protein of bovine papillomavirus (BPV) which is fused to the highly immunogenic HCV core protein or to a string of protein segments (polytope). Laboratory mice will be vaccinated with these VLP and the cellular immune response measured. The vaccine will then be administered to HCV carriers to ensure the safety and the immunological efficacy of the product. This will be assessed serologically and clinically.Read moreRead less