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
The occcurence of herpes simplex virus (HSV) in the general population is very high (up to 60%). In Central Africa, co-infection of HSV and HIV may increase HIV transmission in more than 40% of cases. HSV enters the human body via the skin before entering the termini of nerve cell processes. It is transported along these processes to the body of the nerve cell. HSV lies dormant within these nerve cell bodies near the spinal cord in most people. Intermittently the virus reactivates and is transpo ....The occcurence of herpes simplex virus (HSV) in the general population is very high (up to 60%). In Central Africa, co-infection of HSV and HIV may increase HIV transmission in more than 40% of cases. HSV enters the human body via the skin before entering the termini of nerve cell processes. It is transported along these processes to the body of the nerve cell. HSV lies dormant within these nerve cell bodies near the spinal cord in most people. Intermittently the virus reactivates and is transported back down the nerve cell processes to the skin where it causes blisters-ulcers or is shed without causing symptoms. The aim of this project is to determine how HSV is assembled within cells at the molecular level. This will lead to identification of crucial molecular interactions required for viral assembly. Such information on viral assembly will allow development of inhibitors of this process which may be candidates for use as antivirals for control of recurrent herpes simplex. These antiviral agents will be able to target key viral molecular interactions in essentially all types of cells in the body and act against other herpesviruses in general.Read moreRead less
Functional Roles Of The Tegument Proteins Of Herpes Simplex Virus Type 1
Funder
National Health and Medical Research Council
Funding Amount
$461,597.00
Summary
The occurrence of herpes simplex virus (HSV) in the general population is very high (up to 60%). HSV enters the human body via the skin before entering nerve cells where it lies dormant in most people. Intermittently the virus reactivates and usually forms blisters at the skin when it sheds. The aim of this project is to define a molecular interaction network at the protein level during the course of infection of a host cell. This information will provide new targets for design of antivirals.
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 Human Eukaryotic Translation Elongation Factor 1A Is A Paramyxovirus Virus Dependency Factor
Funder
National Health and Medical Research Council
Funding Amount
$585,497.00
Summary
Several paramyxoviruses cause respiratory disease in infants, young children and the elderly worldwide. Another paramyxovirus that can be contracted by people from infected horses, Hendra virus, is often fatal. There are currently no vaccines against these viruses, and treatment is generally limited to relief of symptoms. In this project we will uncover how these viruses use human proteins for their growth inside cells, with an aim to develop novel therapeutic strategies.
This proposal investigates processes that regulate the cell cytoskeleton to control shape and the dynamics membranes, with a view to developing a generic antiviral therapy. As viruses rely upon the cell cytoskeleton to initiate an infection, we posit that enzymes that control the cytoskeleton can be targeted to block infection.
Transport And Egress Of Herpes Simplex Virus In Neurones
Funder
National Health and Medical Research Council
Funding Amount
$592,023.00
Summary
Herpes simplex virus (HSV) enters the human body via the skin before entering the termini of nerve cell processes. It is transported along these processes to the body of the nerve cell. HSV lies dormant within these nerve cell bodies near the spinal cord in most people. Intermittently the virus reactivates and is transported back down the nerve cell processes to the skin where it causes blisters-ulcers or is shed without causing symptoms. The aim of this grant is to determine how HSV is transpor ....Herpes simplex virus (HSV) enters the human body via the skin before entering the termini of nerve cell processes. It is transported along these processes to the body of the nerve cell. HSV lies dormant within these nerve cell bodies near the spinal cord in most people. Intermittently the virus reactivates and is transported back down the nerve cell processes to the skin where it causes blisters-ulcers or is shed without causing symptoms. The aim of this grant is to determine how HSV is transported within nerve cells at the molecular level. Recent discoveries have shown how virus transport in nerve cells is dependent on interactions between specific viral proteins and cellular motor proteins and how the virus escapes from nerves to infect skin and cause disease. Such information on viral transport will allow development of inhibitors of this process which may be candidates for use as antivirals for control of recurrent herpes simplex. In addition, this information will allow the virus to be exploited for use in gene therapy to introduce DNA into human nerve cells to correct genetic abnormalities. Finally this data will assist in understanding similar mechanisms for other viruses transported in nerve cells such as those causing shingles and rabies.Read moreRead less
Needle Free Delivery Of Dengue And Zika Vaccines To The Skin
Funder
National Health and Medical Research Council
Funding Amount
$642,792.00
Summary
There is no Zika vaccine and only one licensed dengue vaccine, which is age and region restricted because of poor efficacy. We have developed safe subunit vaccine candidates capable of inducing potent virus neutralizing antibodies and demonstrated protection from lethal dengue challenge in a mouse model. Here we are partnering with Vaxxas to undertake preclinical development and GLP toxicity trials for microarray patches delivering dengue and zika virus subunit vaccines.
Hepatitis C virus (HCV) and Human immunodeficiency virus (HIV) infect 200 million and 50 million people world-wide, respectively, and there are no preventative vaccines. The work outlined in this fellowship seeks to understand the structure and function of the major surface proteins of these viruses, their ability to be recognised by the immune system and to develop a novel vaccine for the prevention of HCV.