Adaptation Of Hepatitis C To Host HLA-Restricted Immune Responses In Australian Populations
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
Over 200,000 Australians are infected with the Hepatitis C Virus (HCV) and about 11,000 new infections are diagnosed each year. Around 25% of people infected with HCV will clear the virus while for individuals with chronic infection 10 to 20% will develop cirrhosis of the liver within the next 20-40 years. Differences in host genetic factors and viral variants will, in large part, explain the observed heterogeneity in the clinical outcome and course of HCV infection. The basic theory underpinnin ....Over 200,000 Australians are infected with the Hepatitis C Virus (HCV) and about 11,000 new infections are diagnosed each year. Around 25% of people infected with HCV will clear the virus while for individuals with chronic infection 10 to 20% will develop cirrhosis of the liver within the next 20-40 years. Differences in host genetic factors and viral variants will, in large part, explain the observed heterogeneity in the clinical outcome and course of HCV infection. The basic theory underpinning this research is that the evolution of viruses such as HCV and HIV are influenced by the HLA type of the individual (hots), in combination with the ability of the virus to mutate (rid itself of deleterious mutations) to avoid the host's immune challenge (analogous to drug resistance) even at the lesser cost of impairing viral fitness or replication. We have shown that this is dependent on the immune environment that the virus encounters in relation to which HLA alleles are present in the host, therefore the escape is context specific. After transmission to a new host who lacks the same HLA type, the virus eliminates the previously advantageous mutations which could potentially impair viral fitness. The current study will carry out HCV sequencing and HLA typing on approximately 500 people with HCV from multiple Centres in Australia in order to characterise the interaction between the viral and host genetic factors. A customised software programme, Epipop, has been designed to perform sophisticated statistical analyses on the generated data, and has been successfully applied to HIV vaccine design. The results of this study could help explain why some infected individuals can spontaneously clear their infection while others go on to severe liver disease and allow clinicians to anticipate the course of infection in individuals and plan their management accordingly. Furthermore, the results may facilitate the search for optimal therapeutic and vaccination strategies.Read moreRead less
Understanding The Role Of NS Segments In Evading Influenza A Virus-specific Humoral And T Cell Immunity
Funder
National Health and Medical Research Council
Funding Amount
$213,812.00
Summary
Influenza viruses developed two ways to survive against host immune response: (i) mutating in its genes to escape host immune response, which may cause a new pandemic; (ii) using its NS1 protein to impair host immune response. However, little is known on how these two processes occur and whether NS1 could influence the outcome of escape mutants. By using virological and immunological methods, this study will show how viruses use different NS1 to enhance the viral escape mechanism.
Generation And Persistence Of Effective T Cell Immunity Towards Seasonal And Pandemic Influenza Viruses
Funder
National Health and Medical Research Council
Funding Amount
$451,716.00
Summary
Introduction of a new influenza strain into human circulation leads to a rapid global spread of the virus (e.g. H1N1 2009 pandemic) due to minimal antibody immunity. Established T cell immunity towards conserved viral regions promotes rapid recovery. However, it is unclear what determines the effective T cell immunity towards influenza. We will define the optimal human T cell populations, with the ultimate goal of improving vaccine design so it protects against seasonal and pandemic strains.
Understanding And Controlling Viral Escape In Influenza
Funder
National Health and Medical Research Council
Funding Amount
$433,156.00
Summary
Introduction of a new influenza strain into human circulation leads to a rapid global spread of the virus (e.g. H1N1-09 pandemic) due to minimal antibody immunity. Established T-cell immunity towards conserved viral regions promotes rapid recovery. However, the protective immunity exerts pressure on influenza, leading to "escape" mutations. We will unravel how the viral mutants emerge and propose strategies for T cell-based protective immunity and vaccine design against influenza.
Deciphering IFN Type III, TGF?, IL-10 And Adenosine Pathways In Natural Killer Cells: Enhancing The Innate Anti-metastatic Response Against Breast Cancer Progression
Funder
National Health and Medical Research Council
Funding Amount
$320,891.00
Summary
This project will determine whether one or more factors produced in tumours (eg. cell hormones and metabolites) inhibits NK cells from controlling breast cancer spread using the best available mouse tumour models. We will use genetics to specifically delete response to these factors by NK cells. It is a completely novel approach and this information will allow for the more rational design of cancer treatments following surgery and local radiotherapy and/or chemotherapy.
Professor Godfrey is an immunologist with a long standing history as a pioneer in the study of a specialised type of white blood cell, known as NKT cells. NKT cells are activated in response to lipid-based molecules that are thought to alert the immune system, via NKT cell activation, to the presence of infectious agents or other abnormalities. A better understanding of how NKT cells function will provide new approaches to battling a broad range of diseases where these cells are implicated, incl ....Professor Godfrey is an immunologist with a long standing history as a pioneer in the study of a specialised type of white blood cell, known as NKT cells. NKT cells are activated in response to lipid-based molecules that are thought to alert the immune system, via NKT cell activation, to the presence of infectious agents or other abnormalities. A better understanding of how NKT cells function will provide new approaches to battling a broad range of diseases where these cells are implicated, including cancer, autoimmunity, allergy and infection.Read moreRead less
Characterisation Of Polymorphism In HIV-1 Sequence: Investigation Of Viral Escape From HLA-restricted Immune Responses
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
Although drug therapy has been developed for treatment of HIV infection, there are many aspects of optimal long-term therapy that are problematic. An important reason for this is that HIV disease is different in different individuals, and we believe this is in large part attributable to the way in which the virus can escape an individual's unique immune responses against it. HIV has been shown to escape by mutating and evolving during infection, but the nature and extent to which this occurs in ....Although drug therapy has been developed for treatment of HIV infection, there are many aspects of optimal long-term therapy that are problematic. An important reason for this is that HIV disease is different in different individuals, and we believe this is in large part attributable to the way in which the virus can escape an individual's unique immune responses against it. HIV has been shown to escape by mutating and evolving during infection, but the nature and extent to which this occurs in everyone is not established. This is an important barrier to the design of effective vaccines against HIV. This study uses a novel method to describe the ways that HIV evolves uniquely in every individual, and to determine how this information relates to subsequent disease severity, response to therapy and response to vaccination. This will allow HIV infected patients to have better 'individualised' therapy as well as help in the design of effective vaccines.Read moreRead less
Determining Regulators Of ILC3 In Mucosal Barrier Function And Immune Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$705,209.00
Summary
Innate lymphoid cells (ILCs) are specialized cells that defend the body against invading microorganisms at the body’s surfaces, mediate pathogen clearance and tissue repair but may also drive inflammatory conditions such as allergic asthma and inflammatory bowel disease. We will investigate the molecular switches that regulate this novel cell type and potentially uncover novel molecules or pathways for therapeutic targets.
The Role Of Cytokines In Tumor-induced Immunosuppression
Funder
National Health and Medical Research Council
Funding Amount
$754,473.00
Summary
Cancer-induced immune suppression is a major obstacle to the effective treatment of many cancers. We have shown that the cytokine IL-23, plays an important role in cancer initiation, growth and development. My project aims to characterize the cells that produce IL-23 in the cancer microenvironment and define how it suppresses cells of the immune system. A greater understanding of this cytokine’s mechanism of action will enable the rational improvement of treatments for patients with cancer