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
Novel Generic Vaccine Approaches Applied For The Prevention Of Hepatitis C And Influenza Virus Infections.
Funder
National Health and Medical Research Council
Funding Amount
$392,328.00
Summary
For the induction of good immune responses, antigens should be delivered in several copies on a defined particle. The small envelope protein (HBsAg) encoded by the hepatitis B virus (HBV) has the capacity to self-assemble with host derived lipids into VLPs. HBsAg VLPs are the sole component of one of the most successful vaccines, and clinical trials have shown that they are a successful delivery system for foreign epitopes or protein domains. Hepatitis C virus (HCV) and Influenza viruses are maj ....For the induction of good immune responses, antigens should be delivered in several copies on a defined particle. The small envelope protein (HBsAg) encoded by the hepatitis B virus (HBV) has the capacity to self-assemble with host derived lipids into VLPs. HBsAg VLPs are the sole component of one of the most successful vaccines, and clinical trials have shown that they are a successful delivery system for foreign epitopes or protein domains. Hepatitis C virus (HCV) and Influenza viruses are major human pathogens. HCV has infected 200 million people worldwide, and there is no effective vaccine available. Influenza continues to affect thousands of people each year causing epidemics with severe morbidity and considerable mortality. Current influenza vaccines are mostly inactivated formulations and they exhibit poor immunogenicity in immunological naive persons such as children and in the elderly. The influenza vaccines are not optimal for stimulation of cell-mediated immunity. We propose to use particulate antigens as a delivery platform for influenza and HCV-specific epitopes with the focus to develop approaches to target various HCV and influenza strains, including H5N1 bird influenza. We have successfully produced modified VLPs containing HCV-specific sequences, which are able to induce anti-HCV antibodies with neutralising capacity. We hypothesise that the design of VLPs with an appropriate set of HCV-specific antigens will enhance the neutralising capacity of anti-HCV sera and this may overcome strain specificity. This application will exploit a prototype delivery system to induce antibody and also cellular responses against a variety of HCV- and influenza specific target sequences (epitopes). The outcome of this study will be a prototype multivalent vaccine to a range of HCV- and influenza-specific epitopes. As a delivery system this will be ideal for vaccination against agents that are highly variable.Read moreRead less
The Role Of CXCR3 Chemokines In Hepatitis C And Other Forms Of Viral Hepatitis
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
The majority of individuals infected with hepatitis C virus (HCV) show a slow progression of liver disease over a period of 10-20 years. This liver disease is primarily a result of the host immune response to liver cells (hepatocytes) infected with HCV. As part of this immune response there in an increase in the number of immune cells that infiltrate the liver. To date we do not fully understand the mechanims that attract these cells to the liver but a class of molecules called chemokines is the ....The majority of individuals infected with hepatitis C virus (HCV) show a slow progression of liver disease over a period of 10-20 years. This liver disease is primarily a result of the host immune response to liver cells (hepatocytes) infected with HCV. As part of this immune response there in an increase in the number of immune cells that infiltrate the liver. To date we do not fully understand the mechanims that attract these cells to the liver but a class of molecules called chemokines is the most likely candidate. Thus a greater understanding of the chemokines expressed in the liver, their modulation and role in attracting immune cells to the liver in HCV-related liver disease will help us understand the basic mechanisms of liver disease with the possibility of development of novel therapeutic strategies. In pilot studies we have shown that the chemokine interferon-inducible T cell alpha chemoattractant (I-TAC) is significantly increased in the liver of persons infected with HCV. I-TAC is a member of the CXCR3 ligand chemokine family that attracts lymphocytes to sites of inflammation and as such may play an important role in hepatitis C. We have also shown that hepatocytes express I-TAC and that HCV can upregulate expression of I-TAC in a laboratory model of HCV replication. This proposal plans to determine the molecular mechanisms of I-TAC expression in response to HCV replication and to investigate if I-TAC expression is unique for hepatits C or a general feature of viral infections of the liver. We also plan to determine the the role of I-TAC and other CXCR3 ligand family members in a mouse model of viral hepatitis through the use of CXCR3 ligand antagonists. These experiments will enhance or knowledge of the role of the CXCR3 ligands in hepatitis C and viral hepatitis in general.Read moreRead less
UNDERSTANDING HEPATITIS C VIRUS-SPECIFIC T CELL TOLERANCE
Funder
National Health and Medical Research Council
Funding Amount
$429,710.00
Summary
Most individuals who are infected with hepatitis C virus (HCV) develop a persistent infection that is lifelong and are at risk of developing serious liver disease, including liver cancer. The evidence suggests that an inadequate immune response is responsible for the inability of the patient to resolve the infection, but it is not clear which stage of the immunological cascade might be targeted. In this project, we will test the hypothesis that HCV antigen induce supressor T cells This will have ....Most individuals who are infected with hepatitis C virus (HCV) develop a persistent infection that is lifelong and are at risk of developing serious liver disease, including liver cancer. The evidence suggests that an inadequate immune response is responsible for the inability of the patient to resolve the infection, but it is not clear which stage of the immunological cascade might be targeted. In this project, we will test the hypothesis that HCV antigen induce supressor T cells This will have the effect of inhibiting the immune response and result in the outcome that we currently recognise as persistent HCV infection.Read moreRead less
Hepatitis C Virus infects 3% of the world's population causing recurring liver disease, cirrhosis and hepatocellular carcinoma. To infect a liver cell, the viral glycoproteins attach to cell surface molecules wher they are activated to mediate merger of the viral and cellular membranes. This project grant will explore how the viral glycopropteins become activated and obtain essential structural information on the viral glycoproteins. These studies will help us to design antiviral agents.
Mechanisms Of HIV Binding, Uptake, Trafficking And Infection In Dendritic Cells
Funder
National Health and Medical Research Council
Funding Amount
$144,250.00
Summary
HIV is the fourth greatest killing disease in the world. Currently there are more than 40 million people infected with the virus and it is spreading through Asia, especially India and China. The priorities are vaccines and new antiviral strategies to complement the existing ones and provide alternatives in the event of toxicity and viral resistance to existing drugs. HIV infects three types of body cells, CD4 lymphocytes, macrophages and dendritic cells. Dendritic cells are the key cells which n ....HIV is the fourth greatest killing disease in the world. Currently there are more than 40 million people infected with the virus and it is spreading through Asia, especially India and China. The priorities are vaccines and new antiviral strategies to complement the existing ones and provide alternatives in the event of toxicity and viral resistance to existing drugs. HIV infects three types of body cells, CD4 lymphocytes, macrophages and dendritic cells. Dendritic cells are the key cells which normally act as sentinels at the surfaces of the body picking up microbes digesting them and transferring their products to lymph nodes where the immune response is stimulated. HIV uses this pathway to enter the body and particularly to enter CD4 lymphocytes and lymph nodes and undergo explosive replication. This project is aimed at identifying new proteins which the virus uses to bind to these cells and also the pathways which the virus uses within the cells to be transferred to CD4 lymphocytes. Such knowledge should allow the design of new antiviral strategies and may also assist in developing HIV vaccines.Read moreRead less
Structure And Function Of The Hepatitis C Virus Glycoproteins E1 And E2.
Funder
National Health and Medical Research Council
Funding Amount
$533,828.00
Summary
Hepatitis C virus (HCV) infects approximately 3 % of the global human population with 150,000-200,000 HCV-infected individuals currently living in Australia. Chronic HCV infection is associated with recurrent, progressively worsening liver disease, liver cirrhosis and hepatocellular carcinoma. The current therapy (interferon-ribavirin) is effective in only 40 % of patients and is often associated with severe side-effects. The mechanisms that HCV uses to replicate in liver cells is poorly underst ....Hepatitis C virus (HCV) infects approximately 3 % of the global human population with 150,000-200,000 HCV-infected individuals currently living in Australia. Chronic HCV infection is associated with recurrent, progressively worsening liver disease, liver cirrhosis and hepatocellular carcinoma. The current therapy (interferon-ribavirin) is effective in only 40 % of patients and is often associated with severe side-effects. The mechanisms that HCV uses to replicate in liver cells is poorly understood. In this project we aim to better understand how the viral glycoproteins, E1 and E2, function in the initiation of infection. In particular, we will examine how these glycoproteins bind to liver cell receptors and then mediate virus-cell membrane fusion. These processes lead to the penetration of the HCV genetic material into the cell where it is replicated. These studies are essential for the discovery of new targets for antiviral agents and vaccines.Read moreRead less