Characterize The Post-entry Events Of HIV Infection
Funder
National Health and Medical Research Council
Funding Amount
$605,190.00
Summary
For HIV to successful infect a target cell, it must properly remove the outer layers of its protective gears (outer viral protein coats) to allow the viral genetic materials to be replicate (duplicate and multiplied) for the generation of their ‘offspring viruses’. This process is known as viral uncoating, and it is arguably one of the least understood areas of HIV. In this proposal, we will use a number of complementary state-of-the-arts research tools to characterize the HIV uncoating process.
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.
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.
Structure And Function Of Hepatitis C Virus Glycoproteins
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
Hepatitis C Virus infects approximately 200 million people world-wide and is the major cause of liver transplantation in the Western world. At present there is no vaccine and interferon alpha is the only therapy available and has only limited success in clearing viral infection. HCV is distantly related to flaviviruses eg tick-borne encephaltitis virus and yellow fever virus. All viruses attach to target cells using receptors to initiate the infection process. In the case of HCV, the envelope gl ....Hepatitis C Virus infects approximately 200 million people world-wide and is the major cause of liver transplantation in the Western world. At present there is no vaccine and interferon alpha is the only therapy available and has only limited success in clearing viral infection. HCV is distantly related to flaviviruses eg tick-borne encephaltitis virus and yellow fever virus. All viruses attach to target cells using receptors to initiate the infection process. In the case of HCV, the envelope glycoproteins interact with as yet unknown receptors on the target cell surface resulting in the virus being internalized into endosomes. It is believed that the low pH environment of these endosomes triggers fusion of the viral and cellular membranes. After fusion the genome of the virus is released into target cells and begins the replication process. The actual events intitiating these processes are not understood for HCV but are believed to be mediated using two envelope glycoproteins. In this project we seek to gain a greater understanding of how viral fusion and entry occurs. We have new information regarding the localisation of the two envelope glycoproteins that will now enable us to carefully examine how viral fusion occurs. Using biochemical approaches, we will study their structure and function and examine how this relates to the well understood flavivirus mode of fusion and entry. We will test the functional consequences of altering the structure of the HCV envelope glycoproteins by developing in vitro assays of HCV fusion. Assays for HCV fusion are essential for future studies to identify viral receptors, examine the role of antibody in viral neutralization and can be used to test novel inhibitors of viral fusion and entry.Read moreRead less
Immune Cell Interactions And Cell Signalling Pathways Important For Rotavirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$343,812.00
Summary
Rotaviruses are the main cause of severe diarrhoea in Australian children, through infection of the gut cells that absorb food. This project aims to understand the effects of rotaviruses on the functioning and survival of these cells at the molecular level. It will similarly determine the effects of rotavirus infection on the immune cells. These studies will increase understanding of how rotaviruses cause disease, and assist in the development of drugs or improved vaccines against rotavirus.
HIV Phenotypes Important For The Establishment Of Persistent Reservoirs In The Central Nervous System And Which Impact Neurotropism And Neuropathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$762,492.00
Summary
This grant will determine whether or not the CNS is a reservoir for HIV and identify the cellular targets of persistent infection and type of HIV-1 present.
Delineation Of Receptor-activated Conformational Signalling Pathways In HIV-1 Envelope Glycoproteins
Funder
National Health and Medical Research Council
Funding Amount
$834,478.00
Summary
Although antiretroviral therapy has prolonged the life of people infected with HIV, the virus rapidly develops resistance. Therefore it is essential to develop new antiviral agents to combat HIV infection. The first stages of infection include the process of the virus attaching to cellular receptors and the fusion of viral and cellular membranes leading to entry. In this project we seek to understand how the surface proteins of the virus mediate viral entry and identify new antiviral targets.
Modulation Of Virus-cellular Receptor Interactions In Picornaviral Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$422,036.00
Summary
Gastrointestinal viral infections of humans result in a wide variety of illnesses ranging from the common cold to infantile paralysis and viral myocarditis. Despite the wide range of tissues and organs targeted by these viruses, the manner in which infection is initiated is remarkably similar. The primary step in infection is the binding of a virus to a specific protein on the cell surface, similar to the lock and key analogy. This project seeks to investigate the nature of interactions between ....Gastrointestinal viral infections of humans result in a wide variety of illnesses ranging from the common cold to infantile paralysis and viral myocarditis. Despite the wide range of tissues and organs targeted by these viruses, the manner in which infection is initiated is remarkably similar. The primary step in infection is the binding of a virus to a specific protein on the cell surface, similar to the lock and key analogy. This project seeks to investigate the nature of interactions between representative picornaviruses and their cellular attachment proteins with a view to designing rational anti-viral strategies to block virus cell attachment and cell entry. Using the data raised when investigating why some viruses only infect certain cells, we plan to target human tumors cells based on their susceptibilty to different viruses.Read moreRead less
Structure And Function Of The Hepatitis C Virus Glycoproteins E1 And E2.
Funder
National Health and Medical Research Council
Funding Amount
$533,828.00
Summary
Hepatitis C virus (HCV) infects approximately 3 % of the global human population with 150,000-200,000 HCV-infected individuals currently living in Australia. Chronic HCV infection is associated with recurrent, progressively worsening liver disease, liver cirrhosis and hepatocellular carcinoma. The current therapy (interferon-ribavirin) is effective in only 40 % of patients and is often associated with severe side-effects. The mechanisms that HCV uses to replicate in liver cells is poorly underst ....Hepatitis C virus (HCV) infects approximately 3 % of the global human population with 150,000-200,000 HCV-infected individuals currently living in Australia. Chronic HCV infection is associated with recurrent, progressively worsening liver disease, liver cirrhosis and hepatocellular carcinoma. The current therapy (interferon-ribavirin) is effective in only 40 % of patients and is often associated with severe side-effects. The mechanisms that HCV uses to replicate in liver cells is poorly understood. In this project we aim to better understand how the viral glycoproteins, E1 and E2, function in the initiation of infection. In particular, we will examine how these glycoproteins bind to liver cell receptors and then mediate virus-cell membrane fusion. These processes lead to the penetration of the HCV genetic material into the cell where it is replicated. These studies are essential for the discovery of new targets for antiviral agents and vaccines.Read moreRead less
Elucidating The Mechanisms And Consequences Of Clinical HIV-1 Resistance To The CCR5 Antagonist Maraviroc
Funder
National Health and Medical Research Council
Funding Amount
$622,732.00
Summary
CCR5 antagonists are a new class of anti-HIV drug, and maraviroc (MVC) is the only CCR5 antagonists that is licensed for use as a HIV treatment. Like all HIV treatments, drug resistance to MVC can develop in patients. This study will determine the mechanism of how HIV becomes resistant to MVC, which will permit the development of improved, second generation CCR5 antagonists, and will reveal ways to determine which patients are more likely to develop MVC resistance.