This program application seeks to draw on the skills of a world leading group of Australian researchers to bring novel HIV vaccine designs to clinical trials, improve vaccine design and create new opportunities for commercialisation. The Chief Investigators, Prof David Cooper, Prof Peter Doherty (Nobel Prize winner), A-Prof Stephen Kent and Prof Ian Ramshaw, have achieved major scientific developments including: innovative collaborative clinical trials, cutting edge research in T cell immunology ....This program application seeks to draw on the skills of a world leading group of Australian researchers to bring novel HIV vaccine designs to clinical trials, improve vaccine design and create new opportunities for commercialisation. The Chief Investigators, Prof David Cooper, Prof Peter Doherty (Nobel Prize winner), A-Prof Stephen Kent and Prof Ian Ramshaw, have achieved major scientific developments including: innovative collaborative clinical trials, cutting edge research in T cell immunology, the establishment of the only PC3-level nonhuman primate facility in the Southern hemisphere, T cell immunogenicity of the DNA-viral vector prime-boost vaccine regimens and ground-breaking research on cytokine co-expressing viral vector vaccines. The Principle Investigators also have a record of substantial achievement in relation to HIV and T cell biology as well as novel vaccination technologies. There is a strong history of successful collaboration among this group leading to the award of major NIH funding.Read moreRead less
Critical Role Of TNF In Host-virus Interactions And Outcome Of Infection: Involvement Of Reverse Signalling Through MTNF
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Cytokines are molecules produced by cells that take part in the immune response. They coordinate the activities of leukocytes and are important in the host response to virus infections. For their part, viruses have evolved strategies to try and evade the host response. The analysis of these strategies in the context of a viral infection will lead to a better understanding of the immune system and host-virus interactions. Tumour necrosis factor is a cytokine made by specific leukocytes, in two st ....Cytokines are molecules produced by cells that take part in the immune response. They coordinate the activities of leukocytes and are important in the host response to virus infections. For their part, viruses have evolved strategies to try and evade the host response. The analysis of these strategies in the context of a viral infection will lead to a better understanding of the immune system and host-virus interactions. Tumour necrosis factor is a cytokine made by specific leukocytes, in two stages: First, the cytokine is exposed on the surface of the cell and then it is clipped off and released as a soluble form. In either form it can interact with specific receptors on other cells and, in this way, change the cells' activities. We have found that binding of tumour necrosis factor receptors to the cytokine, while it is in its membrane form, can also send a message backwards into the cell bearing the tumour necrosis factor. This process, known as reverse signalling, then changes the activity of this cell and constitutes a major new route through which information transfer can occur. In this project we will characterize the biological changes that result from reverse signalling in specific types of leukocytes. We will be looking at the role of membrane tumour necrosis factor in two separate models of viral disease. The first is influenza pneumonia that is responsible for a great deal of morbidity and mortality worldwide. The second is a model of poxvirus infection (mousepox) that mimics the disease smallpox in humans. Human poxvirus infections are on the rise (e.g. monkeypox) and there is an increased threat of smallpox as a weapon of bioterrorism. Mousepox is a good model for the study of generalized viral infections and is also an excellent example of a virus that encodes proteins specifically designed to interfere with host tumour necrosis factor. Our studies will focus on the role of this cytokine in host-virus interactions and the outcome of infection.Read moreRead less
Tapasin And Major Histocompatibility Complex Class I Antigen Presentation
Funder
National Health and Medical Research Council
Funding Amount
$226,650.00
Summary
An effective T cell response (cellular immune response) to infections is vital to a functional immune system. Normally, proteins are cleaved into small molecules called peptides and these peptides are in turn presented by Major Histocompatibility Complex molecules to T cells. However, we have only partial understanding of what determines the choice of peptides that are finally presented to T cells. Recent research suggests that a molecule called tapasin may also influence the choice of peptides. ....An effective T cell response (cellular immune response) to infections is vital to a functional immune system. Normally, proteins are cleaved into small molecules called peptides and these peptides are in turn presented by Major Histocompatibility Complex molecules to T cells. However, we have only partial understanding of what determines the choice of peptides that are finally presented to T cells. Recent research suggests that a molecule called tapasin may also influence the choice of peptides. This research proposal aims to examine the role of tapasin in this regard. A thorough understanding of the basic principles of peptide presentation to T cells is crucial to the design of effective vaccines. Furthermore it will also broaden our understanding of immunological responses to cancer, autoimmune diseases and infections.Read moreRead less
Molecular Basis Of T Cell Receptor Bias In Viral Immunity
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
Viral infection results in the activation and proliferation of T cells that eradicate infected cells. Recognition of infected cells is meditated by presentation and recognition of viral protein fragments via specific cell surface receptors. This proposal plans to examine the factors that determine the diversity of the immune response and the consequences of such diversity on anti-viral immunity. This has implications for the development of vaccines.
Dissecting Mechanisms Of Generalised Immune Activation And Cellular Dysfunction In HIV Infection
Funder
National Health and Medical Research Council
Funding Amount
$422,576.00
Summary
How HIV infection compromises the host immune system is still not well understood. We will study how HIV surface proteins contribute to heightened immune activation during chronic infection. This generalised activation eventually leads to dysfunctional cellular immune responses and loss of partial control of infection. We will additionally investigate the extent and impact of the loss of functional immune responses in chronic HIV infection.
Immunological Therapies For Cancer, Chronic Infection And Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$10,891,788.00
Summary
The team comprises five leading scientists with a history of successful investigation into the role of the immune system in cancers, chronic viral infections, and autoimmune diseases. There is a large unmet need for effective solutions with fewer side effects in these diseases which cause a high disease burden in our society. In this program, we particularly seek to develop novel vaccines for chronic infections and autoimmune diseases, and to improve the safety of bone marrow transplantation.
Viral Reservoirs:Role Of Naive T-cells In The Pathogeneisis Of T-cell Decline And Longterm Persistence Of HIV Infection.
Funder
National Health and Medical Research Council
Funding Amount
$85,716.00
Summary
Despite dramatic advances in treatment for HIV infection, HIV cannot be cured. The main reason why cure is not possible is because HIV can persist in long lived cells and these infected cells are not recognised by the immune system. This project will examine the role of a particular type of infection fighting cell, the naive T-cell, in long term persistence of HIV. The project will determine how naive T-cells are infected with HIV and what happens to these cells following HIV treatment.
Competition For Polarity Influences Lymphocyte Differentiation And Function
Funder
National Health and Medical Research Council
Funding Amount
$380,558.00
Summary
CD46 is a protein on human cells that viruses and bacteria bind to during infection. Our laboratory has found that binding of CD46 on immune cells impairs their ability to recognize and kill target cells and may explain the immunosuppression caused by measles infection. We aim to investigate the mechanisms behind the effect of CD46 on immune cells. The outcomes of this study will define new paradigms in lymphocyte biology and determine how CD46 influences the immune response to infection.
Regulation Of Perforin And Granzyme Expression In The Primary Cytolytic T Lymphocyte Response
Funder
National Health and Medical Research Council
Funding Amount
$756,000.00
Summary
The white blood cells known as cytolytic T lymphocytes (CTL) play important roles in elimination of some viruses, bacteria and tumours. Many vaccines and new therapies to prevent or control infections and cancer therefore seek to improve the production and activities of CTL. CTL kill infected cells and tumours by releasing packets of toxic molecules, including the pore-forming protein perforin and enzymes known as granzymes. However, while the roles of perforin and one granzyme, granzyme B, in c ....The white blood cells known as cytolytic T lymphocytes (CTL) play important roles in elimination of some viruses, bacteria and tumours. Many vaccines and new therapies to prevent or control infections and cancer therefore seek to improve the production and activities of CTL. CTL kill infected cells and tumours by releasing packets of toxic molecules, including the pore-forming protein perforin and enzymes known as granzymes. However, while the roles of perforin and one granzyme, granzyme B, in cell killing are now quite well understood, little is known about the other granzymes and how they contribute to immune protection. We have recently discovered that production of perforin and the three most prominent granzymes (A, B and C) can be separately controlled and that they are produced in different levels in different types of immune response. This suggests that they may each serve a different purpose and are therefore required in different amounts depending on the nature of the immune challenge. We have also found that an important hormone of the immune system, interleukin 4, has a profound effect on CTL, preventing their production of perforin and granzymes B and C and hence limiting their ability to kill target cells. In this project we plan a comprehensive analysis of perforin and granzyme production by CTL in response to different signals under controlled conditions in cell culture, and in response to different types of immune challenge in mice. We will also explore how interleukin 4 inhibits perforin and granzyme production and whether this has an impact on the effectiveness of the immune response. Mice in which one or more of the genes coding for perforin and granzymes has been damaged will be used to investigate how the absence of these molecules affects the immune response. We anticipate that these studies will suggest new strategies to improve therapeutic CTL induction by regulating perforin and granzyme production.Read moreRead less