Identification Of Host Restriction Factors That Block Respiratory Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$956,898.00
Summary
Following inhalation, respiratory viruses can infect and grow in airway epithelial cells. Although immune cells such as macrophages are also susceptible to infection, this is generally abortive and new viruses are not released. This project will identify proteins induced in macrophages that block respiratory viruses and prevent their spread in the airways. We will also define mechanisms by which some virulent strains overcome this block to grow in macrophages.
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.
Flaviviruses Must Come Of Age: Design Of Stable, Mature Particles By Structural Vaccinology
Funder
National Health and Medical Research Council
Funding Amount
$1,149,487.00
Summary
We have established a powerful toolset combining advanced structural biology and rapid virus engineering that allows us investigate the assembly of flaviviruses in novel ways. This project will integrate these approaches to investigate the role of new ligands that we have identified in the structure of medically-relevant flaviviruses including dengue virus and delineate a novel maturation path for flaviviruses, which will be used to design safer and more effective flavivirus vaccines.
Assembly Functions Of Respiratory Syncytial Virus Matrix Protein
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Respiratory syncytial virus (RSV) is the single most important cause of lower respiratory infections (pneumonia and bronchiolitis) in young infants. In addition to the morbidity of RSV infection itself, it is well established that symptomatic RSV infection in infancy predisposes to asthma later in life. As all infants are infected by RSV at least once by age 2 yrs, this virus represents a major public health problem. Additionally, re-infection by RSV is increasingly being recognized as a cause o ....Respiratory syncytial virus (RSV) is the single most important cause of lower respiratory infections (pneumonia and bronchiolitis) in young infants. In addition to the morbidity of RSV infection itself, it is well established that symptomatic RSV infection in infancy predisposes to asthma later in life. As all infants are infected by RSV at least once by age 2 yrs, this virus represents a major public health problem. Additionally, re-infection by RSV is increasingly being recognized as a cause of severe lower respiratory disease in the elderly and in immunocompromised patients. The goal of this research is to understand better the mechanisms used by RSV to replicate itself in mammalian cells. Information from this work could be used to design novel antiviral drugs to treat RSV, and novel attenuating mutations that may assist in developing live RSV vaccines. The research focuses on a key viral protein, the matrix (M) protein, which is involved in many steps in virus replication. We aim to understand how M protein interacts with other components of the virus (specifically, envelope proteins) to orchestrate virus assembly. To coordinate assembly of new virus particles, M protein binds to portions of virus envelope glycoproteins and to RSV nucleocapsids (the internal machinery of the virus), bringing them together at the cell membrane. The protein-protein interactions which are responsible for these functions of RSV M protein will be determined.Read moreRead less
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.
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.
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.
Flaviviruses are the agents of many mosquito-transmitted infections such as encephalitis and dengue. Hepatitis C virus is a member of the same virus family. Using Australian flavivirus Kunjin as a model and advanced techniques in molecular biology, biochemistry and electron micriscopy, the research at SASVRC has established international leadership in the area of flavivirus RNA replication and ultrastructure of virus-infected cells. The objectives of this application are to advance further our u ....Flaviviruses are the agents of many mosquito-transmitted infections such as encephalitis and dengue. Hepatitis C virus is a member of the same virus family. Using Australian flavivirus Kunjin as a model and advanced techniques in molecular biology, biochemistry and electron micriscopy, the research at SASVRC has established international leadership in the area of flavivirus RNA replication and ultrastructure of virus-infected cells. The objectives of this application are to advance further our understanding of how the flavivirus RNA replication complex synthesizes RNA and how this RNA is specifically packaged to produce infectious virus. To achieve these goals we will employ state-of-the-art molecular biology techniques based on manipulations with infectious complementary DNA copy of Kunjin virus RNA. The intimate understanding of these mechanisms in flavivirus replication should facilitate the design of efficient antiviral drugs by specifically targeting unique events in RNA replication and-or packaging. This may assist in the development of antiviral drugs for treatment of infections caused by other higly pathogenic flaviviruses in Australia, such as dengue, Japanese encephalitis and Murray Valley encephalitis, and in the rest of the wirld such as New York strain of West Nile virus as well as the related heptitis C virus. Understanding the mechanisms of Kunjin virus replication and assembly will also aid in the further development of this virus as a safe vaccine vector against other viruses, e.g. HIV, and diseases such as cancer.Read moreRead less
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
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