I am an infectious diseases physician and basic scientist interested in the immunopathogenesis of HIV and hepatitis B virus. My work focuses on HIV viral reservoirs and immune reconstitution and the adaptive immune response to hepatitis B virus.
The Role Of Vif In Enhancing HIV Replication And Effecting The Integrity Of The Replication Complexes Of HIV
Funder
National Health and Medical Research Council
Funding Amount
$260,200.00
Summary
HIV-AIDS is still one of the leading causes of infectious human fatality worldwide. The genome of HIV encodes six viral accessory proteins that are necessary for viral replication and infection. One of these genes, viral infectivity factor (vif), is essential for production of infectious virus. Exactly how this viral protein works within the cell is not clear at present. Current literature suggests that Vif acts in some way to enhance reverse transcription, one of the early stages of the viral l ....HIV-AIDS is still one of the leading causes of infectious human fatality worldwide. The genome of HIV encodes six viral accessory proteins that are necessary for viral replication and infection. One of these genes, viral infectivity factor (vif), is essential for production of infectious virus. Exactly how this viral protein works within the cell is not clear at present. Current literature suggests that Vif acts in some way to enhance reverse transcription, one of the early stages of the viral life cycle. We aim to investigate the action of Vif in stabilizing early HIV reverse transcription complexes to understand how it acts to enhance HIV replication and viral infection. The early stages of HIV replication are critical for establishing infection and hence ideal targets for therapeutic intervention. This research will help understand how Vif works in a cell and affects the infectivity of HIV viral particles and may be suggestive of potential targets for development of anti-viral drugs.Read moreRead less
The Tumour Cell-specific Nuclear Targeting Properties Of Chicken Anaemia Virus VP-3: Potential For Anti-tumour Therapy
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
Current trends indicate that cancer will cause 40% of all deaths in Australia by 2012, meaning that new anti-cancer strategies are urgently required. Our proposal intends to examine the subcellular targeting abilities of the unique tumour-cell specific agent apoptin (VP3 - viral protein 3), a small protein encoded by the genome of the chicken anaemia virus. Using various strategies, we have identified part of the apoptin molecule that confers efficient localisation in the nucleus of tumour cells ....Current trends indicate that cancer will cause 40% of all deaths in Australia by 2012, meaning that new anti-cancer strategies are urgently required. Our proposal intends to examine the subcellular targeting abilities of the unique tumour-cell specific agent apoptin (VP3 - viral protein 3), a small protein encoded by the genome of the chicken anaemia virus. Using various strategies, we have identified part of the apoptin molecule that confers efficient localisation in the nucleus of tumour cells, but not non-tumour cells. Our experimental program intends to define this tumour cell-specific targeting signal in detail, and determine the molecular basis of the differential subcellular localisation of apoptin in tumour compared to normal cells. This should contribute fundamental new information regarding the differences between cancer and normal cells. Additionally, we intend to optimise the targeting signal and perform initial experiments to test its efficacy in targeting anti-tumour drugs to the nucleus of tumour cells. Our long-term aim is to use the apoptin tumour cell-specific nuclear targeting signal as part of modular constructs to combat cancer efficiently, and above all, with minimal damage to normal cells and tissues.Read moreRead less
Approaches to combat AIDS and its causative agent, the human immunodeficiency virus HIV-1, have thus far proved ineffective. The proposed research program intends to investigate the nuclear import of two HIV-1 proteins which have central roles in HIV infection. We will apply our expertise in the area of the regulation of nuclear import of viral proteins, and build on our observations with respect to these proteins to attempt to establish the mechanistic basis of their nuclear import, and how thi ....Approaches to combat AIDS and its causative agent, the human immunodeficiency virus HIV-1, have thus far proved ineffective. The proposed research program intends to investigate the nuclear import of two HIV-1 proteins which have central roles in HIV infection. We will apply our expertise in the area of the regulation of nuclear import of viral proteins, and build on our observations with respect to these proteins to attempt to establish the mechanistic basis of their nuclear import, and how this differs from the conventional nuclear import pathways used by normal cellular proteins. We already have evidence that nuclear import of HIV-Tat is regulated in novel fashion by cellular factors, and intend, through determining its mechanistic basis, to be able to form the basis of a strategy to block this import pathway specifically, and thereby inhibit HIV replication. This may form the basis in the future of a new pharmaceutical approach to combat HIV-AIDS.Read moreRead less
Investigation Of The Roles Of TNFa-related Apoptosis-inducing Ligand, TRAIL, In The Immune System.
Funder
National Health and Medical Research Council
Funding Amount
$436,980.00
Summary
TRAIL, is a newly described member of the tumour necrosis factor (TNF)-family of cytokines, which can kill a wide range of tumour cells, and virus infected cells, but not most normal cells. TRAIL has proven to be safe when administered to normal, tumour bearing, and virally-infected mice, and causes no detectable side-effects in these animals. As such it holds huge potential and is being widely investigated for use as a new anti-cancer therapy. Despite these findings, little is known about the t ....TRAIL, is a newly described member of the tumour necrosis factor (TNF)-family of cytokines, which can kill a wide range of tumour cells, and virus infected cells, but not most normal cells. TRAIL has proven to be safe when administered to normal, tumour bearing, and virally-infected mice, and causes no detectable side-effects in these animals. As such it holds huge potential and is being widely investigated for use as a new anti-cancer therapy. Despite these findings, little is known about the true physiological role of TRAIL in vivo. To define the normal roles of TRAIL, CIA has been characterising TRAIL gene knock-out mice. These studies have confirmed that TRAIL contributes to control of tumours in vivo, and in early events during anti-viral responses. However, these studies have also revealed novel roles for TRAIL in T cell biology, and B cell memory. Understanding how TRAIL contributes to these processes, will shed significant light on the potential of TRAIL to be used as a therapeutic agent for humans with lymphoproliferative disease, for illiciting better long-lived antibody responses such as after vaccination, and as an anti-viral reagent in immunocompromised individuals during virus infection.Read moreRead less
Modulating Interactions Between TNFalpha And IGF-1 Signaling Pathways To Reduce Necrosis Of Dystrophic Muscle
Funder
National Health and Medical Research Council
Funding Amount
$476,515.00
Summary
Duchene Muscular Dystrophy (DMD) is a lethal childhood disease that affects mainly boys. These experiments will test new highly specific anti-inflammatory drugs for the potential clinical treatment of muscular dystrophies, using the mdx mouse model of human DMD. It is essential that the benefits of such anti-inflammatory drugs are fully evaluated in long term studies in mice. Two of these drugs (Enbrel and Remicade) are already in wide clinical use for inflammatory disorders and present attracti ....Duchene Muscular Dystrophy (DMD) is a lethal childhood disease that affects mainly boys. These experiments will test new highly specific anti-inflammatory drugs for the potential clinical treatment of muscular dystrophies, using the mdx mouse model of human DMD. It is essential that the benefits of such anti-inflammatory drugs are fully evaluated in long term studies in mice. Two of these drugs (Enbrel and Remicade) are already in wide clinical use for inflammatory disorders and present attractive options for treatment of DMD patients due to their high specificity of action and relatively few side effects. We have shown that both of these drugs have a striking protective effect and reduce necrosis of dystrophic muscle in the mdx mouse. The benefits of these drugs (and the mouse equivalent cVIq) is due to blocking the action of the key pro-inflammatory cytokine Tumour Necrosis Factor-alpha (TNFa). However, the precise mechanism by which high levels of TNFa increase necrosis of dystrophic muscle is not clear. There are many possible pathways. Identifying which is the key pathway(s), is of central importance to design and target new drugs to treat such lethal muscle diseases. Such modulation of signalling is a major therapeutic goal. To determine which mechanism of TNFa action is responsible for muscle necrosis, experiments will investigate several signalling pathways using specific inhibitors: the drug Pifithrin to inhibit p53; soluble RAGE to block RAGE (Receptor for Advanced Glycation Endproducts); and specific inhibitory peptides to block JNK (c-Jun N-terminal kinase). The application of these inhibitors (drugs), in mice, as future therapies for muscle diseases is novel. These studies will provide much new information on TNFa related signalling that is highly relevant to the potential treatment of many diseases, including muscle wasting that is a major problem in the ageing population and in disuse atrophy and cachexia.Read moreRead less
Protein Recognition Of Small RNAs In Innate Immunity
Funder
National Health and Medical Research Council
Funding Amount
$666,417.00
Summary
Protein-RNA interactions are critical in the immune response to virus infections. Small interfering RNAs (siRNAs) are important tools in the discovery of gene function and have great potential for therapy against viral infections and cancer, but can also activate the innate immune system. By characterising the determinants of small RNA sensing by the sensors of the immune system and the protein-RNA interactions involved, we will gain new insights into the design of siRNAs for use in the clinic.
Respiratory Syncytial Virus Matrix Protein-Host Protein Interactions As Targets For Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$686,885.00
Summary
Respiratory syncytial virus (RSV) causes more deaths in winter than influenza, being the major cause of viral pneumonia in infants worldwide, and a potent lower respiratory pathogen in the elderly and immunosuppressed adults. The present proposal will apply a range of techniques to search for new inhibitors of viral infection which target host-virus interactions, as the first step towards new generation anti-viral agents to treat RSV infection.