HIV infection of CD4+ lymphocytes leads to a high rate of reproduction of new virus. However, in the brain, HIV infection of the astrocytes does not yield high levels of new virus. HIV is genetically active in these astrocytes, producing high levels of the messenger molecules, the so-called mRNA, that code for the proteins required for a new virus particle. We have determined that these HIV mRNAs are specifically prevented from translating into protein. The mechanisms controlling protein transla ....HIV infection of CD4+ lymphocytes leads to a high rate of reproduction of new virus. However, in the brain, HIV infection of the astrocytes does not yield high levels of new virus. HIV is genetically active in these astrocytes, producing high levels of the messenger molecules, the so-called mRNA, that code for the proteins required for a new virus particle. We have determined that these HIV mRNAs are specifically prevented from translating into protein. The mechanisms controlling protein translation from RNA are relatively poorly understood compared with the other control points of cellular gene expression, such as the synthesis of mRNA. This project examines how astrocytes rapidly detect the presence of HIV mRNA and alter their translation machinery to halt the expression of HIV protein. This host defence mechanism involves two key components; the cellular component that identifies and responds to the viral mRNA, and the structural features of the HIV mRNA that enable the cell to detect its viral origin. We will study how translation of HIV proteins requires both HIV and cellular factors. We will determine the impact of both viral RNA elements and viral RNA binding proteins on the translation of viral and cellular proteins. The contribution of the type-1 interferons that are produced in response to viral infection will be studied for their role in augmenting the inhibition of HIV protein translation. Since HIV infected astrocytes significantly contribute to the onset of AIDS dementia, we will sees a strategy to lock HIV into a dormant state in the brain and thereby prevent the neurodegenerative disease associated with HIV. We will use the anti-viral mechanism blocking HIV protein translation in astrocytes to protect other cell populations, such as the CD4+ lymphocytes, from HIV infection. These studies will also give insights into the general mechanisms for translational control of gene expression in human cells.Read moreRead less
Avian Influenza: Molecular Basis Of Potential Resistance To Neuraminidase Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$87,250.00
Summary
In this project we will visualize an avian flu protein bound to various antiviral drugs that are currently in the clinic (Relenza and Tamiflu) or are in clinical development. In the immediate term, the images derived from the project will be a valuable predictive tool for evaluating the likely effectiveness of antiviral drugs and vaccines in response to emerging viral resistance. In the longer term the images could be used to guide the development of new antivirals and vaccines against avian flu ....In this project we will visualize an avian flu protein bound to various antiviral drugs that are currently in the clinic (Relenza and Tamiflu) or are in clinical development. In the immediate term, the images derived from the project will be a valuable predictive tool for evaluating the likely effectiveness of antiviral drugs and vaccines in response to emerging viral resistance. In the longer term the images could be used to guide the development of new antivirals and vaccines against avian flu. This initiative brings together Industry leaders in the development of influenza antivirals and vaccines, CSL and Biota, with a leading Medical Research Institute.Read moreRead less
Elucidating The Activation Mechanism Of The HIV-1 Envelope Glycoproteins, Gp120-gp41
Funder
National Health and Medical Research Council
Funding Amount
$636,973.00
Summary
Antiretrovirals prolong the life of HIV+ people, however toxicity and resistance issues persist. We aim to understand how the HIV surface proteins effect viral entry in order to identify new antiviral targets.
The Genetics And Mechanisms Of Resistance To The Zoonotic Highly Pathogenic Influenza Virus In Avian Species
Funder
National Health and Medical Research Council
Funding Amount
$337,373.00
Summary
Highly pathogenic avian influenza (HPAI) poses a serious pandemic risk. This project will investigate the genetic basis and mechanisms underlying resistance to HPAI in birds. It will explore the role of immune genes in resistance to HPAI in six bird species which vary in their susceptibility to HPAI. Functional tests of resistance genes will be performed to determine how these genes can provide resistance to HPAI. This study will assist in the development of strategies to mitigate disease risks.
Blocking Human Cytomegalovirus: Targeting Host Organelle Remodelling And The Viral Assembly Complex
Funder
National Health and Medical Research Council
Funding Amount
$553,477.00
Summary
Human cytomegalovirus (HCMV) is a human pathogen that infects over 60% of adults, is a significant cause of morbidity and mortality in immuno-compromised people, and a major cause of birth defects. Fundamental knowledge gaps remain in understanding host-pathogen relationships during infection. This project will systematically define molecular events giving rise to release of virus from an infected cell, and thereby reveal novel targets to block therapeutically.
The balance between cellular survival and death must be tightly regulated. Cells respond to viral infection by self-destructing, thus limiting viral spread to other cells. Viruses have evolved ways to subvert this defensive cell suicide. This project will define and characterise viral factors that maintain host cell survival during infection. These may be targets for the development of new anti-viral therapies and vaccines.