Mechanisms Of Immune Modulation By Varicella Zoster Virus During Cutaneous Infections
Funder
National Health and Medical Research Council
Funding Amount
$570,446.00
Summary
Varicella zoster virus (VZV) is a herpesvirus which infects up to 90% of the population. VZV causes two skin diseases: chicken pox (varicella) predominantly in childhood and shingles (herpes zoster) in middle to old age people. Whilst VZV usually causes relatively mild disease in healthy individuals, VZV still causes significant morbidity in children and adults. VZV causes life-threatening disease in immunocompromised individuals such as patients who are elderly or have HIV disease. Shingles aff ....Varicella zoster virus (VZV) is a herpesvirus which infects up to 90% of the population. VZV causes two skin diseases: chicken pox (varicella) predominantly in childhood and shingles (herpes zoster) in middle to old age people. Whilst VZV usually causes relatively mild disease in healthy individuals, VZV still causes significant morbidity in children and adults. VZV causes life-threatening disease in immunocompromised individuals such as patients who are elderly or have HIV disease. Shingles affects many elderly individuals and a major complication is prolonged severe pain or post-herpetic neuralgia (PHN), which can be severely debilitating and often requires follow-up medical care for months or even years after the initial attack. Despite its significant impact on the community, little is known about how this virus functions and causes disease. This project aims to improve our understanding of how VZV infection of the skin affects the function of specialised skin cells in order to provide novel information for the development of therapies aimed at lessening the impact of VZV disease on the community. This project has three main components: (1) To determine what the differences are in the types of immune cells present in infected skin from chicken pox and shingles sufferers. (2) To assess the impact of VZV infection on the ability of specialised immune cells (called dendritic cells) to function properly (3) To identify which parts of the virus (called genes) code for functions that interfere with the proper function of specialised immune cells (dendritic cells)Read moreRead less
Immunopathogenesis Of Varicella Zoster Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$346,250.00
Summary
Varicella zoster virus (VZV) is a herpesvirus which infects up to 90% of the population. VZV causes chicken pox (varicella) predominantly in childhood and shingles (herpes zoster) in middle to old age people. Whilst VZV usually causes relatively mild disease in healthy individuals, VZV still causes significant morbidity in children and adults. VZV causes life-threatening disease in immunocompromised individuals such as patients who are elderly or have HIV disease. Shingles affects many elderly i ....Varicella zoster virus (VZV) is a herpesvirus which infects up to 90% of the population. VZV causes chicken pox (varicella) predominantly in childhood and shingles (herpes zoster) in middle to old age people. Whilst VZV usually causes relatively mild disease in healthy individuals, VZV still causes significant morbidity in children and adults. VZV causes life-threatening disease in immunocompromised individuals such as patients who are elderly or have HIV disease. Shingles affects many elderly individuals and a major complication is prolonged severe pain or post-herpetic neuralgia (PHN), which can be severely debilitating and often requires follow-up medical care for months or even years after the initial attack. Despite its significant impact on the community, little is known about how this virus functions and causes disease. This project aims to improve our understanding of how VZV infection affects specialised human cells in order to provide novel information for the development of therapies aimed at lessening the impact of VZV disease on the community. This project has four components: (1) We will continue studies which have shown that VZV causes programmed cell death (apoptosis) in human skin cells (fibroblasts) but not human nerve cells (neurons). We aim to identify viral genes responsible for the cell-type specific modulation of apoptosis in human neurons and fibroblasts (2) We will examine human sensory ganglia (clusters of human nerve cells) during shingles and determine what immune cells are present and whether neurons are undergoing apoptosis (3) To assess the impact of VZV infection on the ability of specialized immune cells (called dendritic cells) to mature properly (4) We have shown that VZV may actively avoid immune detection by interfering with the function of dendritic cells. We aim to identify the mechanism responsible for the virus interfering with the expression of immune molecules which are essential for our immune system.Read moreRead less
Neuropathogenesis Of Varicella Zoster Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
Summary
Varicella zoster virus (VZV) is a herpesvirus which causes chicken pox and shingles. Shingles affects many elderly people and a major complication is prolonged severe pain or post-herpetic neuralgia, often needing follow-up medical care for months to years. Despite its impact on the community, little is known about how this virus functions and causes disease. We aim to improve our understanding of how VZV infects nerve cells to provide new information for the development of new treatments.
Current combination antiviral therapy can't cure an HIV infection because long-lived T-cells carrying latent HIV DNA can rekindle the infection when drugs are removed. We will study elements in HIV genetic code that control expression of HIV proteins from latent HIV. A detailed molecular understanding of the structure and function of these HIV RNA elements and the viral and host cell factors that interact with them will expose new targets for therapy of latent HIV.
Control Of Viral Replication By Non-coding Viral RNA
Funder
National Health and Medical Research Council
Funding Amount
$502,270.00
Summary
In 25 years since identified, HIV-AIDS deaths have exceeded 30 million and 40 million more are now living with HIV. The toll will soon far surpass any other infectious disease epidemic in history, or even military deaths from war in the past century. While effective combination drug therapies are available, multi-drug resistant HIV strains are commonly transmitted, leaving some patients with limited treatment options. New classes of drugs aimed at different steps in virus replication are urgentl ....In 25 years since identified, HIV-AIDS deaths have exceeded 30 million and 40 million more are now living with HIV. The toll will soon far surpass any other infectious disease epidemic in history, or even military deaths from war in the past century. While effective combination drug therapies are available, multi-drug resistant HIV strains are commonly transmitted, leaving some patients with limited treatment options. New classes of drugs aimed at different steps in virus replication are urgently needed. We have discovered that viral RNAs that do not code for protein serve important functions in HIV replication. We will study the molecular mechanisms these non-coding (intron) RNAs previously considered junk use to support of HIV gene expression and assess their potential as drug targets. First, we will investigate the role of these junk RNA loops, or lariat introns, produced in large amounts during the HIV replication cycle. Retroviruses employ RNA splicing to make mRNA for envelope and regulatory accessory genes. The complex alternative RNA splicing pattern of HIV spawns several non-coding lariats, including the lariat-intron that contains much of the removed env coding sequence. We have made the counterintuitive finding that the env-lariat dramatically enhances expression of Env protein. We will examine how this occurs and the involvement of the new class of gene-expression controlling micro-RNAs in this process. We will test for functional activity from the other lariat-introns that are produced by HIV. Second, we will characterise the mRNA-element required for efficient expression of the HIV envelope glycoprotein, Env gp160, which is essential for virus binding and entry during infection. This RNA-element directs the cell protein translation machinery to commence protein synthesis at the start of the Envgp160 rather than at upstream start sites for Vpu and Rev. We will determine how this RNA element works, its structure, and how it might be inactivated.Read moreRead less