Studies On The Flavivirus Nonstructural Proteins And Untranslated Regions Of The Genome Involved In Virus Replication
Funder
National Health and Medical Research Council
Funding Amount
$244,277.00
Summary
Flaviviruses cause potentially fatal diseases of global importance such as yellow fever, Japanese encephalitis (JE) and dengue haemorrhagic fever. Flavivirus disease is also important in Australia with recurrent outbreaks of dengue fever, Australian encephalitis and more recently JE in the northern regions of the continent. Effective vaccines are only available to yellow fever and JE and tick-borne encephalitis and are either live or killed preparations which are potentially hazardous and costly ....Flaviviruses cause potentially fatal diseases of global importance such as yellow fever, Japanese encephalitis (JE) and dengue haemorrhagic fever. Flavivirus disease is also important in Australia with recurrent outbreaks of dengue fever, Australian encephalitis and more recently JE in the northern regions of the continent. Effective vaccines are only available to yellow fever and JE and tick-borne encephalitis and are either live or killed preparations which are potentially hazardous and costly to produce. There are no therapeutic agents (antivirals) available against flavivirus diseases. To produce safe and cost effective vaccines against flaviviruses and to identify targets for antiviral agents, a more complete understanding of how these viruses replicate in the cell and cause disease is required. This investigation aims to define specific aspects of the flavivirus life cycle that are currently unknown.Read moreRead less
Defining The Requirement For The Inhibition Of Bak To The Pathogenesis Of Cytomegalovirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$592,661.00
Summary
Apoptosis, or programmed cell death is a powerful defence mechanism against viral infection. Thus, to replicate efficiently viruses have evolved means to inhibit apoptosis. The central aim of this work is to understand how cytomegalovirus prevents cell death protein during infection. The proposed studies will improve our understanding of the mechanisms that regulate viral replication and will contribute insights into the normal processes that control cell survival.
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.
Polarized Epithelia And The Natural History Of Hepatitis Viruses
Funder
National Health and Medical Research Council
Funding Amount
$358,770.00
Summary
The viruses causing hepatitis in man must cross specialised cell layers in the body to reach the liver, and must again cross these cell layers and liver cells in order to be transmitted to subsequent hosts. This research will examine how each of the hepatitis viruses (HAV to HEV) are able to enter and exit the body, and the role that these mechanisms may play in the development of acute disease and of chronic infections with hepatitis B and C viruses. The findings will contribute to development ....The viruses causing hepatitis in man must cross specialised cell layers in the body to reach the liver, and must again cross these cell layers and liver cells in order to be transmitted to subsequent hosts. This research will examine how each of the hepatitis viruses (HAV to HEV) are able to enter and exit the body, and the role that these mechanisms may play in the development of acute disease and of chronic infections with hepatitis B and C viruses. The findings will contribute to development of improved methods for the prevention and control of viral hepatitis.Read moreRead less
The Role Of Vif In Enhancing HIV Replication And Effecting The Integrity Of The Replication Complexes Of HIV
Funder
National Health and Medical Research Council
Funding Amount
$260,200.00
Summary
HIV-AIDS is still one of the leading causes of infectious human fatality worldwide. The genome of HIV encodes six viral accessory proteins that are necessary for viral replication and infection. One of these genes, viral infectivity factor (vif), is essential for production of infectious virus. Exactly how this viral protein works within the cell is not clear at present. Current literature suggests that Vif acts in some way to enhance reverse transcription, one of the early stages of the viral l ....HIV-AIDS is still one of the leading causes of infectious human fatality worldwide. The genome of HIV encodes six viral accessory proteins that are necessary for viral replication and infection. One of these genes, viral infectivity factor (vif), is essential for production of infectious virus. Exactly how this viral protein works within the cell is not clear at present. Current literature suggests that Vif acts in some way to enhance reverse transcription, one of the early stages of the viral life cycle. We aim to investigate the action of Vif in stabilizing early HIV reverse transcription complexes to understand how it acts to enhance HIV replication and viral infection. The early stages of HIV replication are critical for establishing infection and hence ideal targets for therapeutic intervention. This research will help understand how Vif works in a cell and affects the infectivity of HIV viral particles and may be suggestive of potential targets for development of anti-viral drugs.Read moreRead less
Regulation Of Viral Latency In Gamma-herpesvirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$258,000.00
Summary
The cost to public health from herpesvirus infection is enormous. The gamma-herpesviruses chronically infect more than 95% of the world's population. This group of viruses induce a state of immunosuppression that cause down-regulation of immune responses. This allows the virus the opportunity to evade the immune system and thus survive within the host. The gamma-herpesviruses do not generally cause serious disease in normal individuals but reactivation of gamma-herpesviruses can cause severe dis ....The cost to public health from herpesvirus infection is enormous. The gamma-herpesviruses chronically infect more than 95% of the world's population. This group of viruses induce a state of immunosuppression that cause down-regulation of immune responses. This allows the virus the opportunity to evade the immune system and thus survive within the host. The gamma-herpesviruses do not generally cause serious disease in normal individuals but reactivation of gamma-herpesviruses can cause severe disease, even mortality, in individuals with an immature or a compromised immune system. Viral reactivation is a major complication of immunosuppressive diseases such as HIV (which currently affects more than 45 million people) and in transplant recipients. The virally-induced changes in the host cells can result in the development of secondary infections, post-transplantation lymphoproliferative disease and even the development of tumours. The central aim of the studies described in this proposal is to understand the cellular and viral mechanisms regulating how the virus is maintained in the host. These studies will improve our understanding of how antigen presenting cells and CD8+ T lymphocytes ensure an immune response is maintained and may identify critical targets to facilitate the rational design of antiviral drugs and vaccines.Read moreRead less
Defining The Mechanisms That Regulate Effective Long-term Anti-viral Immunity
Funder
National Health and Medical Research Council
Funding Amount
$547,315.00
Summary
Human cytomegalovirus (HCMV) is a common human pathogen which normally causes a mild or even asymptomatic infection. However, in immunocompromised individuals, HCMV causes severe disease whose manifestations include chorioretinitis, interstitial pneumonia and hepatitis. Similarly, in neonates lacking a fully mature immune system, HCMV causes severe morbidity. Vaccines that protect against HCMV induced cytomegalic inclusion disease have been designated Level I (most favourable) due to the predict ....Human cytomegalovirus (HCMV) is a common human pathogen which normally causes a mild or even asymptomatic infection. However, in immunocompromised individuals, HCMV causes severe disease whose manifestations include chorioretinitis, interstitial pneumonia and hepatitis. Similarly, in neonates lacking a fully mature immune system, HCMV causes severe morbidity. Vaccines that protect against HCMV induced cytomegalic inclusion disease have been designated Level I (most favourable) due to the prediction that they could save lives and prevent life-long disability. Similarly, therapies that prevent and-or reduce HCMV reactivation will significantly improve the prognosis of transplant and AIDS patients. The murine CMV (MCMV) infection model has provided important insights as to how the immune system controls infection, and the mechanisms utilized by the virus to circumvent these processes. The design of effective therapies and vaccines requires a thorough understanding of the mechanisms required to generate and maintain long-lasting anti-viral responses. The studies outlined in this proposal aim to define the impact of specific components of the immune system n the generation, maintenance and effectiveness of anti-viral immunity. The well characterized MCMV model will be used to address these issues.Read moreRead less
Host-virus Interactions That Define The Outcome Of Anti-viral T Cell Responses: Relevance To Viral Persistence
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
Infection with human cytomegalovirus (hCMV) is normally resolved without symptomatic evidence of infection. However, severe hCMV disease can occur in immunocompromised patients in which the manifestations of disease include chorioretinitis, interstitial pneumonia and hepatitis. In immunologically immature children, congenital infection results in cytomegalic inclusion disease (CID). CID in infants causes severe neurological sequelae resulting in mental retardation, deafness and blindness. Vaccin ....Infection with human cytomegalovirus (hCMV) is normally resolved without symptomatic evidence of infection. However, severe hCMV disease can occur in immunocompromised patients in which the manifestations of disease include chorioretinitis, interstitial pneumonia and hepatitis. In immunologically immature children, congenital infection results in cytomegalic inclusion disease (CID). CID in infants causes severe neurological sequelae resulting in mental retardation, deafness and blindness. Vaccination against hCMV induced cytomegalic inclusion disease has been designated Level I (most favourable) due to the prediction that it could save lives and prevent life-long disability. Given the essential nature of CD8 T cells in CMV control and the high prevalence of CMV in society, it will be crucial to develop a vaccine capable of eliciting an efficacious T cell response which develops lasting memory. We hypothesise that mCMV has evolved mechanisms for generating an appropriate T cell response involved in viral control and the establishment of a persistent infection. The central aim of the work in the current proposal is to investigate the cellular and viral mechanisms involved in the generation of cytomegalovirus specific T cells. The proposed studies will improve our understanding of the generation of anti-viral T cell responses and hence will be relevent to further our understanding of the role of T cells in human infection. More importantly the results will provide critical insights into the rational design of suitable antiviral drugs and vaccines.Read moreRead less