Title: Structure of hepadnaviral pre-genomic RNA. We aim to study the replication strategy of human hepatitis B virus (HBV), a member of the hepadnavirus family. Hepadnaviruses infect hepatocytes in the liver and are released in high numbers into the bloodstream. Infection is transmitted by blood or sexual contact. Hepadnaviruses cause acute and chronic infection with varying degrees of liver disease. The HBV DNA genome is formed by copying of a viral pre-genome made of RNA, into DNA. This proce ....Title: Structure of hepadnaviral pre-genomic RNA. We aim to study the replication strategy of human hepatitis B virus (HBV), a member of the hepadnavirus family. Hepadnaviruses infect hepatocytes in the liver and are released in high numbers into the bloodstream. Infection is transmitted by blood or sexual contact. Hepadnaviruses cause acute and chronic infection with varying degrees of liver disease. The HBV DNA genome is formed by copying of a viral pre-genome made of RNA, into DNA. This process is called reverse transcription and is performed by the viral polymerase. Reverse transcription occurs within viral nucleocapsids made of core antigen. After formation of the new viral DNA genome, nucleocapsids are enveloped in surface antigen and are released from the cell. It is assumed that 1 copy of HBV pre-genomic RNA is packaged within each viral nucleocapsid. However, members of the retrovirus family that have common evolutionary origins to hepadnaviruses and also replicate via reverse transcription, contain 2 copies of RNA. The human immunodeficiency virus (HIV), the AIDS virus, is a well-studied example. In HIV infection 2 RNA genomes are packaged into each nucleocapsid and form a dimeric RNA genome. The HIV RNA is able to fold into a series of stem loops that promote formation of dimers. During the reverse transcription step in HIV replication, the polymerase switches templates and forms new combined strains of virus. The project aims to determine if 2 copies of pre-genomic RNA are packaged into HBV nucleocapsids. HBV pre-genomic RNA is able to form stem loop structures similar to those in HIV and has the potential to form dimeric RNA. If 2 copies of HBV pre-genomic RNA are packaged this will allow us to redefine the viral replication strategy and to develop a greater understanding of the relationships between hepadnaviruses and retroviruses. The formation of dimers will also provide a mechanism for recombination between HBV strains.Read moreRead less
Combination Antiviral And Immune Therapies For Hepatitis B Virus Infection.
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Hepatitis B virus (HBV) causes acute and persistent (chronic) infection with varying degrees of liver damage and a strong association with the development of liver cancer. Worldwide ~ 250 million people have persistent HBV infection and while a HBV vaccine is available that protects against infection, current treatments for existing infection are largely ineffective. We wish to study a combination of antiviral drug therapy and vaccination with DNA vaccines, to develop new treatment protocols for ....Hepatitis B virus (HBV) causes acute and persistent (chronic) infection with varying degrees of liver damage and a strong association with the development of liver cancer. Worldwide ~ 250 million people have persistent HBV infection and while a HBV vaccine is available that protects against infection, current treatments for existing infection are largely ineffective. We wish to study a combination of antiviral drug therapy and vaccination with DNA vaccines, to develop new treatment protocols for persistent hepatitis B virus (HBV) infection. The human HBV is a member of the hepadnavirus family that includes a number of other very similar host-specific viruses. Therapies will be tested in ducks infected with the duck hepatitis B virus (DHBV) as these animals provide the only model system available in Australia for development of HBV therapies. DHBV-infected ducks will be treated with a new and extremely potent antiviral drug Entacavir (ETV; Bristol-Myers Squibb). Drug treatment will be combined with various DNA vaccination protocols, including new strategies that involve DNA vaccine priming and recombinant fowlpoxvirus (rFPV) boosting of immune responses. Inoculation of DNA vaccines and rFPV results in expression of viral proteins that are presented to the immune system and evoke strong immune responses. 'Prime boost' protocols with DNA vaccines and rFPV have shown promise for protection against and treatment of human immunodeficiency virus (AIDS virus) infection. We will assess the effect of treatment by measuring levels of DHBV in liver and blood, clearance of infected cells and serological changes. The ultimate aim is to develop successful therapies that can then be applied to treatment and elimination of HBV infection in humans.Read moreRead less
Hepatitis C Virus infects 3% of the world's population causing recurring liver disease, cirrhosis and hepatocellular carcinoma. To infect a liver cell, the viral glycoproteins attach to cell surface molecules wher they are activated to mediate merger of the viral and cellular membranes. This project grant will explore how the viral glycopropteins become activated and obtain essential structural information on the viral glycoproteins. These studies will help us to design antiviral agents.
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
To understand how Hendra virus multiplies in infected cells, we will investigate the structure of its replicative machinery. This will provide the basis for rational drug design increasing Australia’s preparedness against the emergence of Hendra-like viruses.
Identification And Analysis Of Novel Replication Initiation Factors In Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$311,789.00
Summary
Multi-drug resistant Golden staph is a serious medical problem around the world because strains are often resistant to commonly used treatments; new drugs are therefore urgently required. DNA replication is a fundamental process that is essential for the survival of all cellular organisms. This project aims to identify and characterise novel factors involved in DNA replication in Golden staph, which represent potential drug targets.