Molecular Characterisation Of Host Cell Targets Of Human Pathogenic Viruses And Evaluating Their Potential As Novel Therapeutic Targets.
Funder
National Health and Medical Research Council
Funding Amount
$307,946.00
Summary
There are currently no therapeutics to treat victims of Hendra, Nipah or Rabies virus infections, which account for > 50,000 deaths/yr worldwide. Through not fully understood mechanisms, these viruses affect the functions of specific cellular proteins in order to inhibit the host immune system, a process essential to their pathogenicity. We aim to characterise the mechanisms underlying viral inhibition of host immunity and evaluate their potential as novel targets to develop urgently needed t ....There are currently no therapeutics to treat victims of Hendra, Nipah or Rabies virus infections, which account for > 50,000 deaths/yr worldwide. Through not fully understood mechanisms, these viruses affect the functions of specific cellular proteins in order to inhibit the host immune system, a process essential to their pathogenicity. We aim to characterise the mechanisms underlying viral inhibition of host immunity and evaluate their potential as novel targets to develop urgently needed therapeutics against these deadly pathogens.Read moreRead less
A NOVEL MOUSE MODEL TO INVESTIGATE THE MECHANISMS OF VIRUS-INDUCED ARTHRITIS
Funder
National Health and Medical Research Council
Funding Amount
$336,000.00
Summary
We have developed a novel animal model by which to study arthritic disease caused by insect-transmitted viruses known as arboviruses. The existence of this model and novel reagents provides an excellent opportunity to further explore the basic mechanisms of infectious disease in a complete functioning animal, rather than specific cultured cells. The study will use modern approaches in molecular and cellular biology to achieve this goal. The production by our immune systems of soluble mediators ( ....We have developed a novel animal model by which to study arthritic disease caused by insect-transmitted viruses known as arboviruses. The existence of this model and novel reagents provides an excellent opportunity to further explore the basic mechanisms of infectious disease in a complete functioning animal, rather than specific cultured cells. The study will use modern approaches in molecular and cellular biology to achieve this goal. The production by our immune systems of soluble mediators (cytokines-chemokines) and antibodies is an overwhelming positive aspect of our physiological response to infection by microbes. Protection from disease by these immune compounds can happen naturally, or the body's ability to produce these factors can be exploited to our benefit via the administration of vaccines. However, these factors can also be detrimental to the host contributing to severe disease. For instance, work performed almost 40 years ago showed for the first time that under particular conditions, antibodies against viruses can enhance infection, instead of inhibiting infection as normally seen. In the intervening years work by scientists all over the world has associated antibody-dependent enhancement (ADE) of infection to many types of viruses; ADE is even thought to be a risk factor to serious disease with dengue virus, and has been shown in vitro for the AIDS virus and Ebola virus. We have recently discovered a molecular mechanism which explains how antibody enhances viral infection in vitro. In studies on immune cells infected with Ross River Virus (RRV) we found that infection helped by antibody resulted in the specific disruption to the production of cellular chemicals which are toxic to viruses. Are these mechanisms of antibody-enhanced infection also found in animals? Will such mode of infection cause enhanced disease and tissue pathology (arthritis) in animals?Read moreRead less
Molecular Characterization Of Dengue Virus Fusion And Antiviral Inhibitors.
Funder
National Health and Medical Research Council
Funding Amount
$573,557.00
Summary
Dengue viruses are transmitted by mosquitoes and cause major epidemics in more than 100 countries around the world, including Australia. Infection with dengue viruses cause severe and sometimes fatal disease. This proposal focuses on the way dengue virus enters cells and the development of drugs that will prevent virus entry. We have already identified compounds that inhibit the entry process of dengue into cells and this project will significantly build on these early findings.
The Role Of Endocannabinoids In Chronic Hepatitis C
Funder
National Health and Medical Research Council
Funding Amount
$563,002.00
Summary
Hormones related to cannabis help to regulate fat stores in the human body. CB1 antagonists are a new class of drugs that block these hormones and are being tested for the treatment of obesity and fatty liver. We discovered that Hepatitis C makes the liver more sensitive to these hormones, helping the hepatitis C virus to replicate. This project will determine the mechanisms by which CB1 antagonists prevent hepatitis C virus replication and their potential as a novel therapy for this disease.
Improved Treatment Of Congenital Cytomegalovirus Disease Through Study Of Placental Models Of Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$674,918.00
Summary
Congenital CMV is the second most common cause of fetal malformation in Australia, and yet most pregnant mothers do not know about it, nor how to prevent congenital CMV in their baby. It is a viral infection that can severely damage the unborn baby. Our research aims to find more about how the virus damages the baby, and whether antiviral drugs are useful in reducing infection of the baby, and also reducing damage to the baby from such infection. If successful, these studies will be the basis fo ....Congenital CMV is the second most common cause of fetal malformation in Australia, and yet most pregnant mothers do not know about it, nor how to prevent congenital CMV in their baby. It is a viral infection that can severely damage the unborn baby. Our research aims to find more about how the virus damages the baby, and whether antiviral drugs are useful in reducing infection of the baby, and also reducing damage to the baby from such infection. If successful, these studies will be the basis for clinical trials in pregnant women.Read moreRead less
Hepatitis C affects a quarter of a million Australians, causing insidious but progressive liver disease which culminates in liver failure or cancer. There is no vaccine and prevention programs have limited effectiveness, but new antiviral therapies now offer high rates of cure. This Program will evaluate strategies to improve the health of those affected and prevent new infections by better understanding of the virus and the body’s immune response, including scarring and liver cancer formation.
Identification Of Interferon Stimulated Genes That Limit HCV Replication And Predict Therapeutic Outcome
Funder
National Health and Medical Research Council
Funding Amount
$389,224.00
Summary
The only treatment for hepatitis C is Interferon-ribavirin combination therapy. Interferon works by stimulating the liver cells to produce antiviral proteins that can control hepatitis C virus replication, however we do not know which proteins are responsible. The aim of this proposal is to identify those proteins that can limit HCV replication using both a laboratory based and clinical approach and to identify markers that will predict treatment outcome.
Dengue viruses are transmitted by mosquitoes and cause major epidemics in more than 100 countries in tropical and subtropical regions. Infection with Dengue viruses cause Dengue fever or its more severe and sometimes fatal form, Dengue hemmorrhagic fever-Dengue shock syndrome (DHF-DSS). Up to 100 million people are infected annually making Dengue virus one of the most important and frequent mosquito-borne viral diseases worldwide. Over the past two decades, the incidence of Dengue virus infectio ....Dengue viruses are transmitted by mosquitoes and cause major epidemics in more than 100 countries in tropical and subtropical regions. Infection with Dengue viruses cause Dengue fever or its more severe and sometimes fatal form, Dengue hemmorrhagic fever-Dengue shock syndrome (DHF-DSS). Up to 100 million people are infected annually making Dengue virus one of the most important and frequent mosquito-borne viral diseases worldwide. Over the past two decades, the incidence of Dengue virus infection has increased steadily. More than 40% of the world's population is at risk of infection and this number is expected to increase as more people travel. This proposal focuses on the way dengue virus enters cells, specifically the mechanism used by viral proteins to mediate fusion of the viral membrane with that of the host cell. A clearer understanding of the molecular basis of this process should provide potential targets for new drugs that can bind and block this process. In addition, we will also use this information in the design and generation of new vaccine candidates.Read moreRead less
Molecular Interactions Between The Subunits Of The HIV-1 Reverse Transcriptase
Funder
National Health and Medical Research Council
Funding Amount
$347,625.00
Summary
Human immunodeficiency virus type 1 (HIV-1) infection is a serious public health problem affecting millions of individuals world-wide. HIV-1 infection can be controlled or prevented by antiretroviral drugs. However, these drugs eventually become ineffective because the virus can mutate to become resistant to them. Therefore, it is important to identify new targets in the virus life-cycle for chemotherapeutic intervention. A successful target for anti-HIV-1 drugs has been the reverse transcriptas ....Human immunodeficiency virus type 1 (HIV-1) infection is a serious public health problem affecting millions of individuals world-wide. HIV-1 infection can be controlled or prevented by antiretroviral drugs. However, these drugs eventually become ineffective because the virus can mutate to become resistant to them. Therefore, it is important to identify new targets in the virus life-cycle for chemotherapeutic intervention. A successful target for anti-HIV-1 drugs has been the reverse transcriptase (RT) enzyme, which converts the viral RNA genome into a proviral DNA precursor, and is absolutely essential for virus replication. The RT is a dimer consisting of two polypeptides of 66 and 51kDa, and formation of this heterodimer is required for its enzymatic functions. We believe that destabilisation or enhancement of the RT subunits represents a potential target for chemotherapeutic intervention. We have developed a novel system in yeast which we can use to study this interaction and determine any mutations that either enhance or decrease the interaction between the two RT subunits. These mutations will then be assessed for their effects on RT activity and HIV-1 replication. Using this system we have made the novel discovery that certain types of anti-HIV drugs called nonnucleoside reverse transcriptase inhibitors (NNRTIs) can increase the interaction between the two RT subunits. This suggests that increased subunit interaction may, in part, explain the inhibitory activity of RT dimerisation enhancing NNRTIs. Elucidation of the mechanism and structural basis of this phenomenon is of interest to provide insight into the actions of NNRTIs and into the dimerisation process, neither of which is well understood.Read moreRead less