CD4 T-cell Deficiency And Dysfunction In HIV Patients Receiving Effective Antiretroviral Therapy
Funder
National Health and Medical Research Council
Funding Amount
$490,020.00
Summary
Large numbers of people throughout the world will commence antiretroviral treatment for HIV infection over the next 5 years. This treatment partially corrects CD4 T-cell deficiency (the most characteristic immune defect caused by HIV infection) but does not restore the immune system to normal in patients who were very immunodeficient before treatment. This study will determine the cause of residual immune defects in patients receiving antiretroviral drugs with the aim of introducing new therapie ....Large numbers of people throughout the world will commence antiretroviral treatment for HIV infection over the next 5 years. This treatment partially corrects CD4 T-cell deficiency (the most characteristic immune defect caused by HIV infection) but does not restore the immune system to normal in patients who were very immunodeficient before treatment. This study will determine the cause of residual immune defects in patients receiving antiretroviral drugs with the aim of introducing new therapies to correct those defects. Our previous studies have demonstrated that the production of new T-cells in HIV patients receiving antiretroviral durgs is affected by the function of the thymus, but that this does not account for the production of all new T-cells. We will investigate other sites of T-cell production in the body. We have also previously shown that poor recovery of CD4 T-cells in patients successfully treated with antiretroviral drugs is associated with immune activation and that the T-cells do not function adequately, even when CD4 T-cell counts are substantially increased. We will determine whether these abnormalities are the result of a persistent defect in T cell activation by monocytes and-or dendritic cells. The findings of our studies will improve the treatment and life-expectancy of individuals with HIV infection.Read moreRead less
Antibody Mutation Promotes Translocation: A Natural Cause Of Cancer
Funder
National Health and Medical Research Council
Funding Amount
$308,849.00
Summary
During responses to infection, the antibody genes in responding B cells mutate at a high rate, resulting in B cells producing better antibodies. Although essential for long-lived immunity, antibody mutation involves the introduction of DNA breaks which can occasionally cause leukemia or lymphoma. We understand only poorly how DNA repair systems normally make sure that antibody mutation is benign and does not cause cancer.
Cell Division And The Regulation Of Immunoglobulin Switch Recombination At The Molecular Level
Funder
National Health and Medical Research Council
Funding Amount
$392,545.00
Summary
The B lymphocyte is an important cell in the immune response as it generates protective antibody against invading pathogens. The effectiveness of an antibody response partly depends on the type of antibody made (there are eight different types). This attribute alters as the immune response progresses in a poorly understood and highly complex way. However, our recent studies have revealed a simple underlying order that can be dissected using new methods. The key to the underlying simplicity is a ....The B lymphocyte is an important cell in the immune response as it generates protective antibody against invading pathogens. The effectiveness of an antibody response partly depends on the type of antibody made (there are eight different types). This attribute alters as the immune response progresses in a poorly understood and highly complex way. However, our recent studies have revealed a simple underlying order that can be dissected using new methods. The key to the underlying simplicity is a cell division clock used to relate and promote cell changes. Here we intend to apply this new concept and the new methods to dissecting the molecular events associated with linking division to the changing properties of antibody selection. Our aim is to accurately model the process of changing antibody types at both the molecular and whole tissue levels. These studies will give us new insights into how the immune response may be directed to make the most appropriate (effective) response during infection and vaccination.Read moreRead less
Consequences Of Disulfide Exchange In CD4 For Function
Funder
National Health and Medical Research Council
Funding Amount
$332,580.00
Summary
CD4 is a particular type of receptor on the surface of immune cells that participates in our response to infection. CD4 is also the primary receptor for the HIV virus which causes AIDS. We have discovered that a particular type of chemistry is occurring in CD4. This chemistry, which is known as redox chemistry, changes the shape of CD4. The shape change appears to be controlled by the immune cell. We have suggested that the redox chemistry in CD4 is important for controlling how immune cells res ....CD4 is a particular type of receptor on the surface of immune cells that participates in our response to infection. CD4 is also the primary receptor for the HIV virus which causes AIDS. We have discovered that a particular type of chemistry is occurring in CD4. This chemistry, which is known as redox chemistry, changes the shape of CD4. The shape change appears to be controlled by the immune cell. We have suggested that the redox chemistry in CD4 is important for controlling how immune cells respond to infection and how the HIV virus infects immune cells. Moreover, we have designed a small synthetic compound that blocks the redox chemistry in CD4 and prevents HIV infection in the test tube. We propose to investigate how the redox chemistry in CD4 controls the function of immune cells and infection by HIV.Read moreRead less
Pathogenic Role Of MicroParticles In Cerebral Malaria
Funder
National Health and Medical Research Council
Funding Amount
$250,000.00
Summary
Cerebral malaria (CM) is a life-threatening complication of infection caused by parasites. The mechanisms leading to coma, convulsions and death in CM remain unknown. CM in children is associated with high levels of endothelial microparticles (MP). However, not only the levels but also the phenotypes of MP can be altered in CM as well as their related functional properties. The project aims to develop a better definition of the MP released during CM and to study MP phenotypes in relation to clin ....Cerebral malaria (CM) is a life-threatening complication of infection caused by parasites. The mechanisms leading to coma, convulsions and death in CM remain unknown. CM in children is associated with high levels of endothelial microparticles (MP). However, not only the levels but also the phenotypes of MP can be altered in CM as well as their related functional properties. The project aims to develop a better definition of the MP released during CM and to study MP phenotypes in relation to clinical syndrome, disease severity and disease outcome.Read moreRead less
Chronic infections and cancers are major causes of global disease burden. Harnessing the immune system to combat these diseases has proven difficult and cumbersome to date. We invented a new technology to boost the ability of the immune system to fight chronic infections such as AIDS and Hepatitis C. This involves using someone�s own blood treated with sets of short proteins. We term this therapy Overlapping Peptide Pulsed Autologous CelLs (OPAL). This shows great promise in robust animal models ....Chronic infections and cancers are major causes of global disease burden. Harnessing the immune system to combat these diseases has proven difficult and cumbersome to date. We invented a new technology to boost the ability of the immune system to fight chronic infections such as AIDS and Hepatitis C. This involves using someone�s own blood treated with sets of short proteins. We term this therapy Overlapping Peptide Pulsed Autologous CelLs (OPAL). This shows great promise in robust animal models. We now propose to refine this technique in animals in preparation for human clinical trials.Read moreRead less
Development And Function Of NKT Cell Subsets In Humans
Funder
National Health and Medical Research Council
Funding Amount
$533,828.00
Summary
NKT cells are a type of white blood cell that help to control the function of the immune system. Many studies have reported an association between low NKT cell levels and increased rates of cancer and autoimmune diseases such as type 1 diabetes (T1D). Unfortunately, NKT cells are a relatively recent discovery and their function is not well understood, especially in humans. For example, it has only recently been discovered that there are different types of NKT cells with different functions. This ....NKT cells are a type of white blood cell that help to control the function of the immune system. Many studies have reported an association between low NKT cell levels and increased rates of cancer and autoimmune diseases such as type 1 diabetes (T1D). Unfortunately, NKT cells are a relatively recent discovery and their function is not well understood, especially in humans. For example, it has only recently been discovered that there are different types of NKT cells with different functions. This lack of knowledge has prevented us from understanding how NKT cells normally prevent disease, and how we should treat diseases associated with low NKT cell numbers. In this project, we will study human NKT cells to determine how many different subsets exist, how they develop, and what role they play in the immune system. Importantly, we will use our knowledge to compare NKT cells from healthy donors and patient groups with T1D and cancer to determine exactly what is wrong with the NKT cells in these people. While both diseases are already linked to low NKT cell numbers, we do not know how these problems arise, or if some types of NKT cells are more important than others. Our study will determine how different types of NKT cells develop and function in humans and therefore allow a much more detailed understandng of how to diagnose and treat NKT cell deficiencies associated with different diseases.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.
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.