Understanding The Role Of The Scaffolding Protein D13 In Poxvirus Assembly And Its Inhibition By Rifampicin
Funder
National Health and Medical Research Council
Funding Amount
$371,275.00
Summary
Smallpox is one the most notorious diseases in human history. Despite its eradication in the 1970s, human cases of animal poxviruses such as monkeypox virus and the potential use of smallpox as a bioterrorism weapon have called for an improved preparedness of Australia against (re)-emerging poxviruses. This project combines structural biology approaches to understand the complex assembly of poxviruses and provide the basis for the development of broad-spectrum antiviral drugs.
The HIV-1 Spacer Peptide P1: A Novel Anti-retroviral Target
Funder
National Health and Medical Research Council
Funding Amount
$384,000.00
Summary
Human immunodeficiency virus type 1 (HIV-1) is the virus that causes AIDS. The treatment that is in current use, called highly active anti-retroviral therapy (HAART), has significantly delayed the onset of AIDS in HIV-1 infected patients. This therapeutic regimen requires the action of three or more drugs to generate a potency that is sufficient to suppress the virus and restrict outgrowth of resistant mutants. However, even on HAART the virus continues to replicate at a low level, and the threa ....Human immunodeficiency virus type 1 (HIV-1) is the virus that causes AIDS. The treatment that is in current use, called highly active anti-retroviral therapy (HAART), has significantly delayed the onset of AIDS in HIV-1 infected patients. This therapeutic regimen requires the action of three or more drugs to generate a potency that is sufficient to suppress the virus and restrict outgrowth of resistant mutants. However, even on HAART the virus continues to replicate at a low level, and the threat of the development of resistant mutations is ever present. Consequently, additional drug targets are required to continue the successful treatment of HIV-1 infected patients. This research is focused on a large polyprotein produced by HIV called Gag. One end of Gag contains a smaller protein called P1 that is crucial for the ability of HIV to reproduce itself. Small changes to the genetic makeup of P1 (one or two amino acids) lead to a defective virus that cannot replicate. The apparent integral role of P1 in viral replication makes it an excellent target for anti-retroviral therapy. With this project we will further our understanding of P1's role in HIV replication and look at ways we target P1 for the development of effective anti-viral agents.Read moreRead less
Understanding The Assembly Of Poxvirus Immature Particles
Funder
National Health and Medical Research Council
Funding Amount
$315,854.00
Summary
Smallpox is an ancient and dreadful disease that enormously influenced human history causing over 300 millions of deaths in the 20th century only. Human cases of monkeypox virus in the US and the potential use of smallpox as a bioterrorism weapon have called for an urgent improvement in Australia's preparedness against poxviruses. We investigate the assembly of these viruses to advance our fundamental understanding of poxvirus biology and provide rationally designed drugs to fight them off.
Does HIV Function As A Lipid-raft During Infection?
Funder
National Health and Medical Research Council
Funding Amount
$607,289.00
Summary
The exterior surface of HIV has a layer of lipids (a type of fat), which represents approximately 1-3 of HIV by weight. This layer of lipids may serve as a mechanistic trigger, which enables viral components to be systemically released or dispatched from the main structure post-entry to establish successful infection. Completion of this project will define the role of lipids in this process. This new knowledge will be vital to identify new targets to deter the HIV infection process.
Protein Topogenesis And The Assembly/disassembly Of The Enveloped Hepatitis B Virus.
Funder
National Health and Medical Research Council
Funding Amount
$197,884.00
Summary
An estimated 350 million people worldwide, and 250,000 in Australia, are chronically infected with the hepatitis B virus (HBV). Without intervention, one third will die as a direct result of this infection through cirrhosis, liver failure and liver cancer, but current treatments are inadequate. A major obstacle to the study of this virus is the lack of a cell culture infection system. We have used the duck hepatitis B virus (DHBV) model to study the events leading up to assembly of the virus in ....An estimated 350 million people worldwide, and 250,000 in Australia, are chronically infected with the hepatitis B virus (HBV). Without intervention, one third will die as a direct result of this infection through cirrhosis, liver failure and liver cancer, but current treatments are inadequate. A major obstacle to the study of this virus is the lack of a cell culture infection system. We have used the duck hepatitis B virus (DHBV) model to study the events leading up to assembly of the virus in a way which prepares the viral envelope or outer coat for its foray into a new host cell. The project will examine the specific interactions of two proteins, the large and the small envelope protein, in addition to a third envelope protein we have recently discovered, which together make up the viral envelope. This will reveal which envelope components are required to make up the specific structures known to be essential for the disruption of the host cell membrane and subsequent entry of the virus to a new cell. An understanding of the changes that occur to the viral envelope upon entry will enable development of strategies for the inhibition or blocking of this change, thus identifying targets for the development of new antiviral agents. Because HBV is just one of many viruses which have an envelope, all of which must enter the cell in some way, our studies of HBV will also provide new clues with respect to the replication of other viruses such as measles, influenza and HIV. A related part of the study will examine the orientation of the large envelope protein within the virus particle and how it changes its orientation to assume its many important functional roles, in the late stages of particle assembly. Expanding on our finding that the small protein is essential to the orientation of the large protein, this study will reveal the mechanism of a unique method of protein transport which may have wider implications in cell biology.Read moreRead less
Structural Analysis Of Poxvirus Immature Particles And Spheroids
Funder
National Health and Medical Research Council
Funding Amount
$387,489.00
Summary
Despite the eradication of smallpox by vaccination, poxviruses remain a threat to public health because of bioterrorist scares from kept variola stocks and because of the possible emergence of other poxvirus pathogens from the extensive animal reservoir. The structural analysis of the assembly of poxvirus will not only improve our knowledge of fundamental processes, highly conserved in DNA viruses, but could also provide valuable targets for the rational design of antiviral drugs.
Herpesviruses infect most Australians and cause recurrent ulcers, birth defects and cancer. Infection lasts lifelong, and spreads to close contacts without obvious clinical signs. Thus disease is hard to prevent. However we can learn much from related animal infections. We have shown that both mouse and human herpesviruses enter mice via cells in the nose. Thus human infections might follow the same route. We will define what body defences work here and whether vaccines can prevent infection.
Human ?-herpesviruses persist for life, cause cancers and emerge with particular virulence when the immune system is weak. Vaccination against them is therefore an important health priority. We have shown for a related ?-herpesvirus of mice that live vaccines protect. Antibody seems to play a major role. We will test whether safer, recombinant vaccines are also sufficient to elicit protective antibody. Thus we can establish a viable strategy for preventing virus-induced human cancers.
Human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS. Recent advances with combination antiretroviral therapy have prolonged the survival time of HIV-1 infected patients, and provideed two important hints for a strategy to effectively treat this disease. First, administration of a combination of antiretroviral agents that target different stages of the viruses life cycle improves the clinical status of HIV-1 infected patients; and second, the formation of viral particles du ....Human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS. Recent advances with combination antiretroviral therapy have prolonged the survival time of HIV-1 infected patients, and provideed two important hints for a strategy to effectively treat this disease. First, administration of a combination of antiretroviral agents that target different stages of the viruses life cycle improves the clinical status of HIV-1 infected patients; and second, the formation of viral particles during the HIV-1 replication cycle is an effective target for antiretroviral treatment, as demonstrated by the potency of drugs called protease inhibitors. A virus such as HIV is composed of viral proteins as well as genetic material called RNA. Two strands of viral RNA come together during the formation of HIV-1 in a process callered dimerization. It may be possible to interfere with RNA dimerization thus inhibiting HIV replication. This would provide a new target for HIV therapy. In order to do this, the process of RNA dimerization needs to be understood.The focus of this project is to define the mechanism of HIV-1 RNA dimerization, and to identify factors that are critical for virion RNA dimerization. Understanding the mechanism of virion RNA dimerization is likely to provide novel therapeutic target for the development of effective antiviral agents.Read moreRead less
Viral infections of the gut are one of the most debilitating infections one can suffer from. Noroviruses are the most common causative agents of viral-associated gastroenteritis but unfortunately little is known regarding their biology and pathogenesis. Our study aims to investigate the replication and pathogenesis of a mouse norovirus to shed light on similar aspects relating to human norovirus infection. We aim to understand how virus infection in cells leads to disease symptoms.