The Role Of HIV Infection Of Astrocytes In The Development Of HIV Associated Dementia
Funder
National Health and Medical Research Council
Funding Amount
$144,250.00
Summary
Dementia is an extremely common problem in the late stages of Human Immunodeficiency Virus (HIV) infection. HIV-associated dementia is the most common cause of dementia in people under 40 years of age. Despite the development of very good drugs to attack the virus, HIV-associaed dementia continues to be a major clinical problem. We are looking at the reasons why some people infected with HIV become demented and others do not. We are also looking at how best to prevent the development of dementia ....Dementia is an extremely common problem in the late stages of Human Immunodeficiency Virus (HIV) infection. HIV-associated dementia is the most common cause of dementia in people under 40 years of age. Despite the development of very good drugs to attack the virus, HIV-associaed dementia continues to be a major clinical problem. We are looking at the reasons why some people infected with HIV become demented and others do not. We are also looking at how best to prevent the development of dementia. We believe that astrocytes (an important brain cell that supports neurons) play a very important role in the development of HIV-associated dementia. With an improved understanding of the steps leading to dementia we can better plan treatments to prevent the development of this devastating complication of HIV-AIDS.Read moreRead less
Estimation Of Transient Increases In Bleeding Risk Associated With Physical Activity In Children With Haemophilia
Funder
National Health and Medical Research Council
Funding Amount
$102,143.00
Summary
Haemophilia A and B are genetic conditions which affect 1 in 7,000 males in Australia. These disorders cause frequent bleeding due to problems with the clotting factor in blood. Over the past decade there has been a move to administer clotting factor to children with haemophilia in order to prevent bleeds and the consequent damage to joints that occurs when bleeds occur in a joint. Participation in vigorous physical activity and sport is thought to increase the risk of bleeding. Because of this, ....Haemophilia A and B are genetic conditions which affect 1 in 7,000 males in Australia. These disorders cause frequent bleeding due to problems with the clotting factor in blood. Over the past decade there has been a move to administer clotting factor to children with haemophilia in order to prevent bleeds and the consequent damage to joints that occurs when bleeds occur in a joint. Participation in vigorous physical activity and sport is thought to increase the risk of bleeding. Because of this, children are often given clotting factor prior to playing sport. However clotting factor is extremely expensive. For example, a boy wanting to play tennis three times a week would require three injections of cIotting factor per week at a cost of approximately $250,000 a year. To date there is no good evidence about which physical activities are likely to increase the risk of bleeding. If this information was available clinicians would be able to optimise timing of administration of clotting factor so that it is administered prior to activities associated with high risk of bleeds. Another reason to quantify risk of bleeds associated with activity is to inform decisions about participation in physical activity. Every boy with haemophilia wants to know if he can play sport or ride a skateboard or jump on a trampoline. Informed decisions about participation require accurate estimates of risk. This study will use an innovative design to provide, for the first time, accurate estimates of the risk of bleeding associated with physical activity. This information will form the basis for clinical practice guidelines regarding participation in physical activity.Read moreRead less
Drug Resistance Mutations In The Connection Subdomain Of The HIV-1 Reverse Transcriptase
Funder
National Health and Medical Research Council
Funding Amount
$376,710.00
Summary
Human immunodeficiency virus type 1 (HIV-1) infections can be controlled with antiretroviral drugs. In the majority of patients on antiretroviral therapy the virus mutates and is no longer inhibited by the drug. The emergence of drug-resistant HIV-1 is one of the major factors that lead to loss of drug efficacy in patients. Mutations that confer drug resistance have been defined and are specific for different drug classes. Genotype assays that are used to predict drug resistance are routinely us ....Human immunodeficiency virus type 1 (HIV-1) infections can be controlled with antiretroviral drugs. In the majority of patients on antiretroviral therapy the virus mutates and is no longer inhibited by the drug. The emergence of drug-resistant HIV-1 is one of the major factors that lead to loss of drug efficacy in patients. Mutations that confer drug resistance have been defined and are specific for different drug classes. Genotype assays that are used to predict drug resistance are routinely used to guide therapeutic decisions in the treatment of HIV-1 infected individuals. For drugs that target the HIV-1 reverse transcriptase (RT), commonly used genotype kits normally analyse mutations in the first 240 out of 560 amino acids of the reverse transcriptase. This ignores the impact of mutations in other regions of the enzyme, which are potentially important in drug resistance. Recently, mutations that inhibit ribonuclease H function of the HIV-1 RT have been shown to confer high-level resistance to zidovudine, providing the precendent that mutations beyond codon 240 can confer drug resistance. Our analysis of a different region to ribonuclease H called the connection subdomain has demonstrated the presence of mutations that are highly prevalent in drug-treated versus drug naive patients. In this study we will use in vitro assays to define the effect of these mutations on drug resistance and viral fitness . We will also determine the mechanism by which these mutations confer drug resistance. Finally, using our unique database consisting of over 20,000 genotyped samples , we will establish the role of these mutations in the patient. This study is anticipated to identify clinically significant mutations that are present in the RT connection subdomain. Additionally, this study will lead to the development of more accurate genotype assays which will improve the clinical management of HIV infected individuals.Read moreRead less
SERPINB2 IS AN INDUCIBLE HOST FACTOR INVOLVED IN ENHANCING HIV-1 TRANSCRIPTION AND REPLICATION
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
SerpinB2 is one of the most abundant proteins made at sites of inflammation. We have shown that HIV-1 infection also induces SerpinB2 and that SerpinB2 then helps the virus to replicate. In this grant we seek to understand how the virus causes this protein to be made and how this protein then increases virus replication. In the human population there are different forms of SerpinB2 and this grant seeks to determine whether these different forms affect HIV-1 replications differently. It may for i ....SerpinB2 is one of the most abundant proteins made at sites of inflammation. We have shown that HIV-1 infection also induces SerpinB2 and that SerpinB2 then helps the virus to replicate. In this grant we seek to understand how the virus causes this protein to be made and how this protein then increases virus replication. In the human population there are different forms of SerpinB2 and this grant seeks to determine whether these different forms affect HIV-1 replications differently. It may for instance be possible that an individual who has a certain form of SerpinB2 may be less susceptable to AIDS following HIV-1 infection.Read moreRead less
Downregulation Of N-myc Oncogene Expression As A Therapeutic Strategy For Childhood Neuroblastoma.
Funder
National Health and Medical Research Council
Funding Amount
$145,990.00
Summary
Neuroblastoma is a common cancer of young children which, despite the use of powerful anticancer drugs that cure other childhood cancers, has only a 40% survival rate. Many laboratories have shown that the most aggressive neuroblastoma tumours, which are most resistant to the action of anticancer drugs, have an abnormal number of copies of a cancer-associated gene, called N-myc. Patients whose tumours have multiple N-myc copies have dismal survival prospects, and new treatments for such patients ....Neuroblastoma is a common cancer of young children which, despite the use of powerful anticancer drugs that cure other childhood cancers, has only a 40% survival rate. Many laboratories have shown that the most aggressive neuroblastoma tumours, which are most resistant to the action of anticancer drugs, have an abnormal number of copies of a cancer-associated gene, called N-myc. Patients whose tumours have multiple N-myc copies have dismal survival prospects, and new treatments for such patients are urgently needed. Several studies, using models of neuroblastoma cells growing in the laboratory, have shown that it is possible to create small fragments of genetic material which can specifically switch off the N-myc gene. When this happens, the neuroblastoma cells behave in a less aggressive and malignant way. We have recently shown that these genetic fragments are capable of reducing the growth of tumours in mice which have been genetically manipulated to develop neuroblastoma. We now want to develop new types of genetic fragments (DNAzymes) that will be even more effective at switching off N-myc and inhibiting neuroblastoma development, because these fragments may be extremely valuable for treating neuroblastoma in patients.Read moreRead less
Inhibition Of Nef-activated Src-family Kinases By CHK
Funder
National Health and Medical Research Council
Funding Amount
$514,307.00
Summary
HIV hijacks infected blood cells to produce its own proteins. Nef is one of these proteins and Nef alone is sufficient to cause an AIDS-like disease. Recently, we discovered that a protein called CHK can inhibit Nef. Our research will determine how CHK inhibits Nef and test the feasibility of drugs based on CHK. Such drugs would slow AIDS progression, assisting conventional therapies and patients' immune systems to combat the infection, leading to longer, healthier, more productive lives.
The Use Of Minimal Residual Disease Detection To Improve Treatment Outcome In Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Available evidence suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of alternative therapy when the c ....Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Available evidence suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of alternative therapy when the cancer burden is at a low level, has a high likelihood of improving patient survival. The failure to respond well to treatment is assessed by a novel molecular genetic technique developed in our laboratory that can detect and quantitate very low levels of residual leukaemia with great sensitivity and specificity. The major goal of this project is to conduct a clinical trial in which this testing procedure is used at an early stage of treatment, and patients who have a bad result on this test, will be given more intensive treatment to see if this improves survival rates. In addition, the project is also directed towards investigating a range of genes known to have a role in drug detoxification. A number of naturally occurring variations exist for these drug metabolising genes and there is evidence suggesting that specific variations or patterns may influence a cancer's response to treatment. We will therefore examine the genetic patterns present in a large cohort of leukaemias and correlate these patterns with response to treatment. It is anticipated that these studies will help define the most appropriate treatment strategies for children with leukaemia. This project therefore has major implications for the therapeutic management of children with leukaemia and has the potential of contributing directly to the improved survival of this most common of childhood cancers.Read moreRead less
Processes Underlying Establishment And Maintenance Of The Latent HIV Resevoir And Potential Impact Of Integrase Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$318,044.00
Summary
Therapy for HIV-infected individuals is currently able to control the growth of the virus, but cannot eradicate the viral infection. This is due to a pool of CD4+ T lymphocytes which contain HIV DNA in a latent state, ready to reactivate as soon as therapy is interrupted. This project aims to better understand how this pool of latently infected CD4+ T lymphocytes is established and maintained, particularly how it is linked to the essential T cell survival signal from interleukin 7.
Controlling HIV-1 Replication In Macrophages: Cellular Regulation Of Tat Expression
Funder
National Health and Medical Research Council
Funding Amount
$466,500.00
Summary
Monocytes in the blood and macrophages in the tissues are the scavenger cells of the body's immune system. They are among the first cells to become infected with HIV and harbour the virus for the lifetime of the cell, which can be up to several years. While monocytes are only infected at low frequency, macrophages in tissues can be infected in high numbers and can contribute significantly to virus production. Current potent combination therapies are unable to clear the virus from these cells and ....Monocytes in the blood and macrophages in the tissues are the scavenger cells of the body's immune system. They are among the first cells to become infected with HIV and harbour the virus for the lifetime of the cell, which can be up to several years. While monocytes are only infected at low frequency, macrophages in tissues can be infected in high numbers and can contribute significantly to virus production. Current potent combination therapies are unable to clear the virus from these cells and have limited efficacy in this cell type. There are no treatments which specifically target HIV infection in these important viral reservoirs. We have found that in a laboratory model of HIV infection in macrophages, the infection changes from active and productive to chronic and non-productive over the course of several weeks. This change is characterised by a decrease in one of the virus' important regulatory proteins, Tat. In this project, we aim to determine how the cells induce this change in the virus' growth. This may lead to novel ways in which HIV could be controlled in these important cells by targeting cellular rather than viral proteins. Controlling infection in macrophages and preventing spread of the virus to other cells would assist with the problem of the virus rebounding rapidly when patients stop or interrupt therapy and would help with long term treatment and management, leading to eventual eradication of the virus from the body.Read moreRead less
The Use Of Minimal Residual Disease Detection To Improve Treatment Outcome In Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$374,625.00
Summary
Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Evidence obtained by ourselves and others, suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of altern ....Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Evidence obtained by ourselves and others, suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of alternative therapy when the cancer burden is at a low level, has a high likelihood of improving patient survival. In this regard, we have recently developed a novel molecular genetic technique that can detect and quantitate very low levels of residual leukaemia with great sensitivity and specificity. This technique is ideally suited for use in the routine clinical setting, and as a result of this development, we have now established a clinical trial (ANZCCSG Study VIII) in which patients who have a bad result on this test, will be given more intensive treatment to see if this improves survival rates. A number of research questions will also be addressed in this trial including whether the level of residual leukaemia at the end of therapy is able to predict future relapse that would otherwise not be suspected. It is anticipated that the clinical trial will help define the most appropriate treatment strategies for children with leukaemia. This project, which is at the forefront of such studies worldwide, has major implications for the therapeutic management of children with leukaemia and has the potential of contributing directly to the improved survival of this most common of childhood cancers.Read moreRead less