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.
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
Envelope Glycoprotein Determinants Underlying Cytopathicity Of CCR5-restricted Human Immunodeficiency Virus Type 1
Funder
National Health and Medical Research Council
Funding Amount
$428,602.00
Summary
HIV weakens the immune system causing AIDS, but the mechanism by which HIV does this are poorly understood. This proposal aims to define these mechanisms. We expect that HIV evolves in infected people, becoming better able to infect and kill cells of the immune system, and that this results from specific genetic changes in the virus. This study will contribute to a greater understanding of how HIV causes AIDS, which is necessary for the development of new drugs to treat HIV infection.
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.
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.
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
Molecular Studies Of The Astrocyte Reservoir Of HIV-1 In The Central Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$592,661.00
Summary
HIV infects the brain causing dementia in 10-20% patients. Strategies aimed at eradicating HIV infection fail to take into account CNS infection. Understanding the way in which HIV enters, infects and replicates in the brain is pivotal in development of drugs to prevent brain infection and dementia. Our studies have shown that HIV infection of the brain involves mechanisms distinct to those observed for blood and other organs. This study seeks to clarify such mechanisms.
Molecular Studies Of The Astrocyte Reservoir Of HIV-1 In The Central Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$533,828.00
Summary
Human immunodeficiency virus type 1 (HIV-1) causes AIDS and, to date, has infected approximately 20 thousand people in Australia and more than 40 million worldwide. HIV infects the central nervous system and causes HIV associated dementia in 10-20% of patients with AIDS. Despite the introduction of highly active antiretroviral therapy the prevalence in Australia continues to rise and studies have shown that the incidence has been under represented in the South east Asian region. Infection of the ....Human immunodeficiency virus type 1 (HIV-1) causes AIDS and, to date, has infected approximately 20 thousand people in Australia and more than 40 million worldwide. HIV infects the central nervous system and causes HIV associated dementia in 10-20% of patients with AIDS. Despite the introduction of highly active antiretroviral therapy the prevalence in Australia continues to rise and studies have shown that the incidence has been under represented in the South east Asian region. Infection of the CNS has two major implications for the treatment of AIDS patients. Firstly, HIV-associated dementia is the most common cause of dementia in people under 40 and this continuing increase in the number of young adults with dementia is placing increased pressure on health resources in the community. Secondly, strategies aimed at eradicating HIV infection from AIDS patients have thus far have failed to take into account the important and unique viral reservoir present in the CNS of an infected patient. The mechanisms involved in HIV-1infection of the brain remain unclear. Understanding the mechanisms by which HIV enters, infects and replicates the brain, are pivotal to the development of regimes to prevent infection of the brain in the first instance as well as development of targeted drug therapy to prevent dementia. Our preliminary studies have shown that HIV infection of the brain involves unique HIV virus and cellular mechanism distinct to those observed for the blood and other organs. This study seeks to clarify such mechanisms. This study will contribute to a greater understanding of how HIV-1 enters the brain and causes dementia, both of which are essential to the development of new drugs to treat HIV-1 infection.Read moreRead less