Determination Of The Mechanisms Of Action Of A Cytomegalovirus Chemokine Receptor Homologue In Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$251,341.00
Summary
A number of herpesviruses encode proteins that are similar to proteins of our immune system. These pirated proteins are exploited by the virus to enable it to replicate and persist in the infected individual, usually by evading or gaining advantage from the normal immune response. This project will investigate the role of one such protein found in both human and animal herpesviruses (specifically cytomegaloviruses (CMV)) that is conserved with cellular cell surface proteins (receptors) that bind ....A number of herpesviruses encode proteins that are similar to proteins of our immune system. These pirated proteins are exploited by the virus to enable it to replicate and persist in the infected individual, usually by evading or gaining advantage from the normal immune response. This project will investigate the role of one such protein found in both human and animal herpesviruses (specifically cytomegaloviruses (CMV)) that is conserved with cellular cell surface proteins (receptors) that bind immune signaling molecules (chemokines). Chemokines are important proteins in the early response to infection. Binding of chemokines to their receptors initiates a cascade of signals within the cell that has profound effects on cellular responses to environmental stimuli. Thus, it is believed that herpesviruses have acquired chemokine receptors to modify or react to the immune response, causing infected cells to behave abnormally either despite or in response to chemokine signals. This project will determine how this CMV specific protein affects the function of cells that CMV infects and how this may promote virus replication, dissemination and persistence in infected hosts. We will also engineer CMVs where the activity of the target protein can be inhibited by administration of prototype antiviral drugs. If inhibition of the activity of the protein is found to reduce virus replication, dissemination or persistence, then this will demonstrate that this type of protein would be a suitable target for the development of novel drugs active against CMV infections. CMV can cause serious (potentially life threatening) disease in newborn children (following infection in the uterus) and immunosuppressed people (eg. organ transplant recipients and people with HIV-AIDS). Our studies will improve our understanding of the contribution of a specific CMV protein to disease, thereby assisting efforts to reduce the impact of CMV infections.Read moreRead less
Inhibitors Of West Nile Virus Protease As Antiviral Drugs
Funder
National Health and Medical Research Council
Funding Amount
$590,740.00
Summary
The West Nile Virus (WNV) was first isolated from a woman in the West Nile region of Uganda in 1937. It is one of ~70 known flaviviruses (e.g. Dengue fever, Yellow fever, West Nile, Kunjun, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, Australian encephalitis and the related hepatitis C virus) which annually infect hundreds of millions of people worldwide, particularly in tropical and sub-tropical areas, and cause major public health problems. WNV is endemic in people i ....The West Nile Virus (WNV) was first isolated from a woman in the West Nile region of Uganda in 1937. It is one of ~70 known flaviviruses (e.g. Dengue fever, Yellow fever, West Nile, Kunjun, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, Australian encephalitis and the related hepatitis C virus) which annually infect hundreds of millions of people worldwide, particularly in tropical and sub-tropical areas, and cause major public health problems. WNV is endemic in people in the Middle East, parts of Africa and Europe, but recent epidemics in Israel (1998), Romania (1996), United States (1999), and UK (2003), that have been traced to migratory birds, were characterized by severe symptoms , severe neurological pathology, and fatalities. In the USA alone there were 4,156 infections and 284 deaths in 2002, 9122 infections and 223 deaths in 2003, and this mosquito borne virus has quickly spread since 1999 through all USA states and into Canada and Mexico (http:--www.cdc.gov-ncidod-dvbid- westnile-index.htm). No treatments or vaccines are available. This project focuses on a viral enzyme, known as the West Nile Virus NS3 protease, that is essential for replication of the virus. By studying the enzyme in the laboratory we can design small molecules that block its function and these are potential leads for developing drug treatments for people infected, not only by this virus but potentially also other flaviviruses. A precedent is the success of inhibitors of HIV-1 protease that are the most effective treatment for humans with HIV-infections, and other viral proteases are now becoming recognized as viable antiviral targets for pharmaceutical development. The project involves experts on small molecule protease inhibitor design and development, proteases, and virology including West Nile virology. We expect to generate new information at the cutting edge of West Nile Virus and flavivirus research and promising new antiviral drug candidates.Read moreRead less
Hepatitis B Virus Drug Resistance: Impact On The Immunisation Program
Funder
National Health and Medical Research Council
Funding Amount
$113,322.00
Summary
ñAntiviral drug-associated vaccine escape mutantsî have the potential to jeopardize the hepatitis B immunization program. Which particular viral mutations or combination of mutations that can directly affect the clinical outcome of infection, especially in the context of vaccine induced immunity, are not known. In this study we will identify the clinical sequelae and public health consequences arising from the selection of these mutants.
Novel Antivirals For The Treatment Of Hendravirus Infection.
Funder
National Health and Medical Research Council
Funding Amount
$199,227.00
Summary
Hendravirus outbreaks have become frequent and 7 human cases have been reported, this has resulted in 4 deaths. Currently we have no treatment options. Researchers at Griffith University and the CSIRO have developed a new treatment that attacks the virus by turning off the viral genes at the site of infection. The plan is to treat patients soon after infection to slow or stop the virus and allow patients to recover naturally from this highly lethal disease.
Determining The Clinical Effectiveness Of Antiviral Drugs Against Oseltamivir- And Laninamivir-resistant Influenza Viruses In Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$388,067.00
Summary
Currently, the neuraminidase inhibitors are the only drugs that are effective against seasonal influenza viruses. However, viruses can develop resistance to these drugs. Using viruses with varied levels of resistance, the project will determine the effectiveness of different drug treatments in animal models. This will lead to better treatment for those patients seriously ill with drug-resistant influenza viruses.
Combining Laboratory And Computational Approaches To Develop Reliable Low Cost HIV Prognostics
Funder
National Health and Medical Research Council
Funding Amount
$314,644.00
Summary
Certain anti-HIV drugs called "CCR5 antagonists" block HIV entry into immune cells. However, HIV drug-resistance can occur. Globally, patient access to CCR5 antagonists has been limited because the pre-treatment laboratory test required to determine HIV drug-resistant is expensive and time-consuming. My research will lead to development of computer programs that reliably, rapidly and cheaply determine HIV drug-resistance and thus greatly improve patient access to CCR5 antagonists worldwide.
Targeting Novel Sites On Reverse Transcriptase For HIV Treatment And Prevention
Funder
National Health and Medical Research Council
Funding Amount
$978,994.00
Summary
HIV/AIDS remains a major global threat with 37 million individuals living with HIV in 2014. Antiretroviral drugs have transformed HIV from a death sentence into a chronic disease. Public health organisations recommend dramatic scale up of drugs for HIV treatment and prevention. However, a major threat is that drug options will be exhausted due to drug resistance and toxicity. The major aim of this study is to undertake fundamental studies to advance the development of a new HIV drug class.
Roles Of Virus-integrin Interactions And Rotavirus Modulation Of Host Cell Responses In Viral Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$474,000.00
Summary
Rotaviruses are the main cause of severe gastroenteritis in children, and cause 1 in 27 Australian children under the age of 5 years to spend time in hospital. There is currently no rotavirus vaccine available. We aim to discover how rotavirus interacts with host cells. This information is necessary to formulate a safe and effective vaccine, or a therapeutic agent that can block virus growth in host cells. Previously, we showed that rotavirus attaches to cells and enters them using several membe ....Rotaviruses are the main cause of severe gastroenteritis in children, and cause 1 in 27 Australian children under the age of 5 years to spend time in hospital. There is currently no rotavirus vaccine available. We aim to discover how rotavirus interacts with host cells. This information is necessary to formulate a safe and effective vaccine, or a therapeutic agent that can block virus growth in host cells. Previously, we showed that rotavirus attaches to cells and enters them using several members of the integrin protein family that are present on the surface of the cells. Integrins are critical for cell adhesion, survival and communication. In this project, we will identify how rotavirus usage of integrins modulates cell functions. This will help us understand how rotavirus causes disease, how virus spreads in the body and how the immune response defends us from rotavirus. Rotavirus binds integrins using particular stretches of protein sequence that we have shown are also present in other human viral pathogens that cause hepatitis, AIDS and measles. We will determine if these other viruses also recognize integrins.Read moreRead less
Retroviral Recombination, RNA Dimers & Multiple Drug Resistant HIV-1
Funder
National Health and Medical Research Council
Funding Amount
$405,017.00
Summary
The emergence of multiple drug resistant strains of HIV-1 has threatened the continue success of current clinical treatment to suppress virus propagation. Retroviruses, such as HIV-1, can reshuffle its two copies of genetic materials during the viral replication process, which leads to the production of offspring viruses that contain a mixture of the parental genetic materials. This process of genetic information reshuffling is believed to be important for the generation of multiple drug resista ....The emergence of multiple drug resistant strains of HIV-1 has threatened the continue success of current clinical treatment to suppress virus propagation. Retroviruses, such as HIV-1, can reshuffle its two copies of genetic materials during the viral replication process, which leads to the production of offspring viruses that contain a mixture of the parental genetic materials. This process of genetic information reshuffling is believed to be important for the generation of multiple drug resistant strains of HIV-1. The objective of this proposal is to define the parameters that regulate the reshuffling of HIV-1 genetic materials and to design novel tools to inhibit the production of multiple drug resistant HIV-1.Read moreRead less
Towards A New Class Of Reverse Transcriptase Inhibitor For HIV Prevention
Funder
National Health and Medical Research Council
Funding Amount
$688,833.00
Summary
There remains an urgent need for new HIV prevention strategies. New HIV drugs that block the virus by distinct ways are needed to prevent transmission of drug resistant HIV. This study seeks to identify very small molecules called “fragments” that bind to previously undiscovered pockets on the HIV reverse transcriptase to stop its function, and that can be used as building blocks to design more potent HIV drugs to be used solely for HIV prevention.