The Role Of Subgenomic Non-coding Viral RNA In Flavivirus Pathogenicity
Funder
National Health and Medical Research Council
Funding Amount
$555,325.00
Summary
Flaviviruses are transmitted by insects and pose a serious health threat to the Australian population. They can cause fever syndromes, encephalitis and death. We aim at better understanding of how these viruses cause disease. We are particularly interested in elucidating the role of small non-coding nucleic acid produced by flaviviruses in the viral pathogenicity. Ultimately, this deeper understanding should lead to the development of effective vaccines and antiviral therapies.
We seek to gain a detailed understanding of how interactions between the West Nile virus proteins and host factors involved in the IFN response determine the outcome of virus infection. Better understanding of the mechanisms employed by this highly pathogenic virus to disable the mammalian host's IFN response will have wider implications for our understanding of other human diseases such as cancer, autoimmunity and provide new avenues for design of efficient antiviral and anticancer therapies.
Escape And Reversion Of Critical Immune Responses: Insights Into Effective Immunity To HIV
Funder
National Health and Medical Research Council
Funding Amount
$372,446.00
Summary
The HIV pandemic is a global emergency. The overall goal of this grant proposal is to elucidate the requirements for protective immunity to HIV. Although immune responses have some effect on HIV replication, the virus mutates and evolves to escape immune pressure. However, each mutation away from wild-type virus likely results in at least some impairment in the ability of the virus to replicate. Where efficient immune responses target regions of the virus that are critical to virus replication, ....The HIV pandemic is a global emergency. The overall goal of this grant proposal is to elucidate the requirements for protective immunity to HIV. Although immune responses have some effect on HIV replication, the virus mutates and evolves to escape immune pressure. However, each mutation away from wild-type virus likely results in at least some impairment in the ability of the virus to replicate. Where efficient immune responses target regions of the virus that are critical to virus replication, escape mutations may result in viral variants incapable of causing disease. Resulting from an exciting collaboration between HIV and theoretical biologists, we have recently identified techniques to calculate the effectiveness of immunity and the cost of subsequent immune escape variants. We will use and expand these techniques to identify immune responses that result in the most effective control of viral replication. These studies will lead to ways to improve HIV vaccines and thereby prevent HIV.Read moreRead less
AIDS is caused by the human immunodeficiency virus type 1 (HIV-1). Long-term HIV infection leads to increased incidence of Kaposi's sarcoma, AIDS dementia complex, and immune dysfunctions. The HIV-1 Tat protein has been linked to disease progression. However, Tat is predominantly found in the cell nucleus while measurable levels in patient serum. This is not believed to be a passive event caused by dying cells. Here we will investigate how Tat is released by HIV-1 infected cells.
Immunopathological Role Of Monocyte-macrophages In Flavivirus Encephalitis.
Funder
National Health and Medical Research Council
Funding Amount
$445,011.00
Summary
Viral encephalitis is a life-threatening infection of the brain for which there are no reliable treatments. White cells called monocytes enter the brain from the blood and although important in the immune response that destroys the virus, can also damage the brain. Our work focuses on determining how monocytes migrate into the brain in viral infection, what functions they have once inside the brain, and how to exclude a certain types of monocytes that we have found to be particularly damaging.
Lipocalin 2 In Host Defence Of The Central Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$575,014.00
Summary
Lipocalin 2 is a protein that is involved in protection of the host organism against bacterial infections. We have found that high levels of lipocalin 2 are produced by a variety of cells in the brain in response to not only bacterial products but also to infection with West Nile virus (WNV). WNV is a dangerous virus known to cause lethal encephalitis. This project will determine the role of lipocalin 2 in the defence of the host against WNV encephalitis.
Identification And Quantification Of HIV Latency Biomarkers In The Central Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$814,618.00
Summary
One major obstacle in curing HIV is the brain’s role as a potential reservoir of HIV infection. It is unknown if “reawakening” of HIV may lead to uncontrollable brain damage given that current antiretroviral drugs vary in their ability to treat brain infection. Not all patients have HIV brain infection so eradication therapies in themselves may be safe. We aim to identify and quantify biomarkers of HIV latency in the brain to stratify patients into these two cohorts.
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