The HIV-1 Tat Protein Is An Reverse Transcription Co-factor.
Funder
National Health and Medical Research Council
Funding Amount
$404,592.00
Summary
HIV-1 is the virus that causes AIDS. In order for HIV-1 to grow, the viral genetic material must be converted into a form that is compatible with a human host. Specifically, the HIV-1 genetic material is made of RNA while the human genome is composed of DNA. An HIV-1 enzyme called reverse transcriptase (RT) is used for this purpose. We have discovered that another HIV-1 protein called Tat is also required for the efficient conversion of HIV-1 RNA into HIV-1 DNA. If HIV-1 lacks Tat, then this tra ....HIV-1 is the virus that causes AIDS. In order for HIV-1 to grow, the viral genetic material must be converted into a form that is compatible with a human host. Specifically, the HIV-1 genetic material is made of RNA while the human genome is composed of DNA. An HIV-1 enzyme called reverse transcriptase (RT) is used for this purpose. We have discovered that another HIV-1 protein called Tat is also required for the efficient conversion of HIV-1 RNA into HIV-1 DNA. If HIV-1 lacks Tat, then this transformation process is inefficient and HIV-1 is not able to grow. Recently our group made a breakthrough discovery on how Tat works. Tat can directly bind to RT and stimulate the conversion process. This research is aimed at a detailed analysis of Tat and RT interaction. This information is required in order to understand how this interaction can be blocked in order to stop HIV-1 growth. In the long-term, results produced by this research will be required to discover novel drugs to combat HIV-AIDS.Read moreRead less
Worldwide there are approximately 40 million people living with HIV-AIDS. An effective HIV vaccine does not exist at present. Therefore, current strategies to control the HIV pandemic include the use of life saving antiretroviral drugs. While the current drugs are successful in controlling infections, new and more effective agents are needed that inhibit HIV replication by distinct mechanisms due to the inevitable development of drug resistant strains of HIV. The HIV reverse transcriptase enzyme ....Worldwide there are approximately 40 million people living with HIV-AIDS. An effective HIV vaccine does not exist at present. Therefore, current strategies to control the HIV pandemic include the use of life saving antiretroviral drugs. While the current drugs are successful in controlling infections, new and more effective agents are needed that inhibit HIV replication by distinct mechanisms due to the inevitable development of drug resistant strains of HIV. The HIV reverse transcriptase enzyme is essential for HIV replication and has been a successful target for nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). NNRTIs act in part by stabilizing the reverse transcriptase enzyme, thus blocking enzyme function. However, no drugs have been developed that can specifically prevent formation of the reverse transcriptase enzyme, which would result in the production of noninfectious viral particles. We propose that formation of the active reverse transcriptase enzyme, from a large polyprotein called Gag-Pol, proceeds through a homodimer intermediate, which represents an ideal target for blocking reverse transcriptase formation in HIV infected cells. This homodimer intermediate is an attractive target with greater potential for disruption with small molecule inhibitors compared to the mature reverse transcriptase enzyme as it is less stable than the reverse transcriptase found in viruses. This study will determine whether formation of the active RT enzyme is dependent on this intermediate. In addition, we will examine how the reverse transcriptase encoded on Gag-Pol regulates activation of the HIV protease, which is also critical for the formation of infectious virus particles. These studies will increase our understanding of how the virus produces infectious particles and will identify new approaches for targeting the HIV reverse transcriptase enzyme.Read moreRead less
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
The Role Of The Inflammasome In Modulating Disease During Influenza Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$616,979.00
Summary
Highly pathogenic influenza A virus (IAV) infections in humans are associated with high mortality rates. This project will provide global and fundamental insights into our understanding of why IAV often cause fatal disease. It will advance knowledge of the mechanisms by which the host and virus interact and elucidate how the host's immune system responds to the infection and modulates disease, to facilitate the development of improved treatments for severe IAV infections.
The Role Of Noncoding Viral RNAs In Flavivirus Infection And Exosomal Signalling
Funder
National Health and Medical Research Council
Funding Amount
$683,447.00
Summary
The application is aimed at investigating the novel role for viral noncoding RNAs in exosomal antiviral signalling and associated outcome of infection with West Nile virus. We will identify host enzymes involved in generation of viral noncoding RNAs, determine which host proteins they interact with and how these interactions determine their incorporation into secreted exosomes to influence outcome of infection.
NEW INSIGHT INTO GLYCAN REQUIREMENTS FOR ROTAVIRUS-CELL ATTACHMENT AND ENTRY
Funder
National Health and Medical Research Council
Funding Amount
$1,068,758.00
Summary
Rotavirus causes significant infection and loss of life in children, particularly in underdeveloped countries. This project will investigate the role of carbohydrates as contact points for this deadly virus towards the goal of developing novel vaccines and drug therapies.
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.
Molecular Pathogenesis Of Emerging West Nile Viruses
Funder
National Health and Medical Research Council
Funding Amount
$594,133.00
Summary
West Nile virus (WNV) is a mosquito-borne virus that causes potentially fatal encephalitis in humans and horses. This project will investigate the recent emergence of pathogenic for horses WNV in Australia and the potential of this new isolate to cause severe disease in humans. We will define the viral and host factors determining the outcome of WNV infection. This project will provide knowledge on the factors involved in the emergence of virulent WNV strains from attenuated isolates.
Defining A Virally-encoded Molecular Switch Between Productive And Latent Phases Of Human Cytomegalovirus Infection.
Funder
National Health and Medical Research Council
Funding Amount
$337,614.00
Summary
Human cytomegalovirus (HCMV) is a significant human pathogen which causes serious disease in immunosuppressed people such as bone marrow and solid organ transplant patients. HCMV has the capacity to switch between an active and a dormant state, enabling this virus to remain within the human host, where it can emerge years later to cause disease in immunosuppressed people. This project will define how HCMV controls the switch between active and dormant phases of infection.
Host Genes Controlling Flavivirus Infection: New Insights And Application For Developing Highly Effective Kunjin Replicon-based Ebola Vaccine
Funder
National Health and Medical Research Council
Funding Amount
$736,995.00
Summary
The applications is aimed at identifying new host genes controlling infection with West Nile virus and other medically important flaviviruses such as dengue and Japanese encephalitis. For this, we will use novel in vivo RNAi screening approach with virus libraries encoding artificial microRNAs (amirs) targeting whole mouse genome. We will then apply amiR technology to produce highly effective Kujniin replicon-based Ebola vaccine candidate that has shown promising results in trails in primates.