Immune Correlates Of Protection Against HCV - A Potential Role For NK Cells And NKR Expression On T Lymphocytes
Funder
National Health and Medical Research Council
Funding Amount
$72,754.00
Summary
Hepatitis C virus (HCV) poses a major public health problem with ~200 million people infected worldwide and no available vaccine. Injecting drug users (IDUs) are the major risk group, with 75% of infected individuals progress to chronic infection, which can then lead to liver cirrhosis and hepatocellular carcinoma. However, about 20% of a given cohort of IDUs remains uninfected. This project is therefore focused on understanding the innate immune mechanisms behind this protection.
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
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
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
Evaluation Of Naturally Occurring Resistance To Direct Acting Antiviral Drugs (DAAs) In Individuals With Acute Hepatitis C Infection
Funder
National Health and Medical Research Council
Funding Amount
$333,778.00
Summary
Hepatitis C therapy in the future is likely to involve the use of Directly Acting Antivirals, which offer a better chance of treatment success and shorter treatment courses. The downside to these new agents is the possible development of drug resistance. Studies suggest that drug resistant strains may already exist in some individuals prior to treatment. This study plans to use sensitive methods to examine how common drug resistant strains are in untreated individuals with acute hepatitis C.