Impact Of HIV Infection And Treatment With Highly Active Retroviral Therapy On Reverse Cholesterol Transport
Funder
National Health and Medical Research Council
Funding Amount
$339,375.00
Summary
HIV has been found to be associated with increased risk of cardiovascular diseases. The introduction of new treatment for HIV resulted in a dramatic improvement in morbidity and mortality of HIV-infected patients, but paradoxically cardiovascular complications became more frequent and severe. It is not currently clear whether increased cardiovascular risk is due to long lasting HIV or due to the impact of therapy. In both cases a major complication of HIV and-or therapy is rapid development of a ....HIV has been found to be associated with increased risk of cardiovascular diseases. The introduction of new treatment for HIV resulted in a dramatic improvement in morbidity and mortality of HIV-infected patients, but paradoxically cardiovascular complications became more frequent and severe. It is not currently clear whether increased cardiovascular risk is due to long lasting HIV or due to the impact of therapy. In both cases a major complication of HIV and-or therapy is rapid development of atherosclerosis. Atherosclerosis is the cause of more than half of heart diseases, which is a leading cause of death in Western societies. Atherosclerosis develops when cholesterol is deposited within artery walls, causing the formation of a fatty plaque and restricting blood flow. The mechanism behind the effect of HIV and its treatment on development of atherosclerosis is unknown. This project is designed to investigate how and why HIV infection and its treatment results in this increased risk of cardiovascular disease.Read moreRead less
This project will determine how viruses prevent transmission of messages within cells which orchestrate responses of our immune system to infection and whether our current therapies improve this defect. This knowledge will help us to better understand why our immune system is not able to control chronic virus infection and improve therapies for these diseases.
Role Of The Thymus In T Cell Homeostasis During Foetal And Postnatal Life In Sheep
Funder
National Health and Medical Research Council
Funding Amount
$264,750.00
Summary
The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cells, has considerable implications for the development of a pool of T cells able to respond to a large number of infections. Recent thymic emigrants represent a wide diversity of positively selected thymocytes exhibiting newly arising T cell specificities, but mature T cell pool e ....The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cells, has considerable implications for the development of a pool of T cells able to respond to a large number of infections. Recent thymic emigrants represent a wide diversity of positively selected thymocytes exhibiting newly arising T cell specificities, but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a limited number of clones. It follows that a mixing of the pool of older mature T cells with new ones just released from the thymus will introduce more variability, and hence greater adaptability into the immune system. We have developed techniques for labeling the thymus in vivo and the entire blood leukocyte pool in vivo using the long-term lymphocyte tracking dye CFSE. We can establish a cohort of labeled cells and we can, for the first time in any experimental system, track directly the survival, death or division of recent thymic emigrants and mature cells and their progeny together with their tissue homing properties and surface markers for periods of many months. This will enable us to determine the way in which the pool of mature T cells is built up during the formation of the foetal immune system and the way the mature T cell population is established and maintained in postnatal life.Read moreRead less
Pathogenesis Of Antiretroviral Induced Sub-cutaneous Fat Wasting
Funder
National Health and Medical Research Council
Funding Amount
$331,650.00
Summary
The use of potent antiretroviral therapy has resulted in great clinical and survival benefit in patients with HIV infection and has in most cases, outweighed the risk of short term side effects. However, not that survival of patients with AIDS has considerably improved the long-term complications of chronic therapy have become a critical issue. Lipodystrophy syndrome(s) is the name given to a set of changes to blood lipids, glucose levels and body habitus and typically occurs in those successful ....The use of potent antiretroviral therapy has resulted in great clinical and survival benefit in patients with HIV infection and has in most cases, outweighed the risk of short term side effects. However, not that survival of patients with AIDS has considerably improved the long-term complications of chronic therapy have become a critical issue. Lipodystrophy syndrome(s) is the name given to a set of changes to blood lipids, glucose levels and body habitus and typically occurs in those successfully treated with anti-HIV therapy. The facial and body habitus changes are common, progressive and are frequently disfiguring. Aside from the psychological and social effects of such changes, many patiens are not able to retain their anonymity as HIV infected individuals. In addition, changes to blood lipids may lead to atherosclerosis. Already there have been several case reports of premature coronary disease in young HIV infected patients. It is increasingly difficult for patients to remain strictly adherent to chronic therapy because of all these concerns. There is an urgent need to understand the exact biological cause(s) of lipodystrophy syndrome(s) in HIV infected patients in order to help identify which of our currently available antiretroviral therapies will offer the long term clinical and survival benefit of strong viral suppression without increasing risk of vascular disease. Based on results of our previous studies on lipodystrophy syndrome, we have proposed that lipodystrophy may be the result of antiviral drugs depleting the DNA content of mitochondria within fat cells. We propose to examine sequential fat biopsy specimens from HIV infected volunteers to determine whether antiretroviral therapy has had adverse effects on mitochondrial DNA content and-or function.Read moreRead less
Changes In The Fate Of Thymic Emigrants During Foetal And Postnatal Development In Sheep
Funder
National Health and Medical Research Council
Funding Amount
$62,744.00
Summary
SIGNIFICANCE The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cell, has considerable implications for the development of the T cell repertoire. Recent thymic emigrants represent a wide diversity of positively selected thymocytes but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a l ....SIGNIFICANCE The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cell, has considerable implications for the development of the T cell repertoire. Recent thymic emigrants represent a wide diversity of positively selected thymocytes but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a limited number of clones. A high rate of continuous substitution of mature T cells in the peripheral pool with freshly arriving recent thymic emigrants exhibiting newly arising TCR not previously existing will produce higher adaptive capabilities for the immune system. We have developed techniques for labeling the thymus in vivo by intra-thymic injection with the long-term lymphocyte tracking dye CFSE. We can establish a cohort of labeled recent thymic emigrants and we can, for the first time in any experimental system, track directly the survival, death or division of recent thymic emigrants and their progeny together with their tissue homing properties and surface markers for periods of many months after they leave the thymus. This will enable us to determine the way in which the pool of mature T cells is built up during the formation of the foetal immune system and the way the mature T cell population is established and maintained in postnatal life.Read moreRead less
A Longitudinal Study Of Natural Killer Cell Function In HIV-infected Individuals Initiating Therapy
Funder
National Health and Medical Research Council
Funding Amount
$620,176.00
Summary
HIV infected people no longer die from AIDS but suffer and die from non-AIDS conditions such as non-AIDS related cancers. We have discovered persistent abnormalities in natural killer cells in HIV patients receiving antiretroviral therapy. These cells help prevent the development of and control cancers so understanding why they are abnormal in HIV patients will help prevent early death from non-AIDS cancers.
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.
HOST CELL FACTORS INCREASE THE EFFICIENCY OF HIV-1 REVERSE TRANSCRIPTION
Funder
National Health and Medical Research Council
Funding Amount
$636,919.00
Summary
We have found that when human immunodeficiency virus (HIV) infects a cell, it uses functions of the host to better infect. At this point, we do not know the identity of the host cell factors involved. If we are able to identify the factors we might be able to specifically target them without affecting normal cell functions. This approach has the advantage that it minimises the opportunities for the virus to develop drug resitance, which is increasingly a problem with HIV.
Whole Human Genone Expression Analysis In CD4+ CD8+ T Cells And Monocytes At Various Stages Of HIV Disease
Funder
National Health and Medical Research Council
Funding Amount
$380,558.00
Summary
HIV is an important global problem and what happens to human gene machinery at the level of different cell types upon contact with HIV remains unclear. We have a novel approach of analysing whole human genome expression in relation to HIV in diverse blood cell types. Identification and understanding of key genes will provide insights into how restoration of the host immune system could be achieved in the future in combating HIV infection and possible cure.