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.
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
HIV currently infects ~40 million people world-wide, causing ~3 million deaths in 2003, mainly in the world's poorest countries. A cheap, effective vaccine seems the best means of preventing the spread of the epidemic. The two main approaches to vaccination are either to make antibodies (which bind to and inactivate the virus), or killer T cells (which kill infected cells). Many of these vaccines are now being tested in monkeys. The results of killer T cell vaccination trials have been both enco ....HIV currently infects ~40 million people world-wide, causing ~3 million deaths in 2003, mainly in the world's poorest countries. A cheap, effective vaccine seems the best means of preventing the spread of the epidemic. The two main approaches to vaccination are either to make antibodies (which bind to and inactivate the virus), or killer T cells (which kill infected cells). Many of these vaccines are now being tested in monkeys. The results of killer T cell vaccination trials have been both encouraging and disappointing. The vaccines do not appear able to prevent the monkeys from getting infected with the virus. However, in many cases even though the monkeys become infected with HIV, they do not get the usual disease associated with AIDS, and hence live with rather than die from this infection. The aims of this project are to use statistical analysis, and more complex mathematical and computer models to try to analyse the data generated by these vaccine trials and to understand how these partially effective vaccines help control virus. For example, even if a vaccine does not prevent infection, we can investigate whether it slowed viral growth, or increased killing of infected cells, and if so, whether an increase in this response could be effective. In preliminary work we have analysed data from a vaccination trial performed in Boston. The results of this study suggest that the reason vaccinated monkeys still become infected is that the killer T cells produced by the vaccine do not appear to activate for the first 10 days of infection. In these first 10 days the virus grows normally and is able to establish a foothold for continuing infection. By contrast, we find that antibodies act extremely early after infection. The methods we propose have not been used before to study vaccines, and by studying the kinetics of the virus and immune response from a large number of vaccine trials we hope to help identify the optimal vaccine design.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.
Adaptive Changes In HIV-1 Subtype C Envelope Glycoproteins Contributing To Pathogenicity.
Funder
National Health and Medical Research Council
Funding Amount
$427,648.00
Summary
HIV exists as multiple subtypes. The most commonly studied is type B (B-HIV). B-HIV is common in North America, Europe and Asia, but accounts for only a small fraction of HIV infections worldwide. Type C HIV (C-HIV) in Africa and Asia accounts for the majority of infections worldwide, yet very little is known about how C-HIV causes AIDS. We aim to understand how C-HIV causes AIDS. This is critical for development of drugs and vaccines specifically designed for those who are most urgently need.
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
Transposable Element Mobility And Chromosomal Rearrangement In The Fungal Pathogen Cryptococcus During Human Infection
Funder
National Health and Medical Research Council
Funding Amount
$322,028.00
Summary
Pathogenic fungi present in the environment have emerged as an increasingly common threat to human health. Cryptococcus neoformans and the closely related species Cryptococcus gattii are the leading causes of life-threatening fungal meningitis, and Australia is one of the few countries where both species are prevalent. Although C. neoformans is an increasingly common cause of infection in immunocompromised patients such as those suffering from AIDS, approximately one in four infected individuals ....Pathogenic fungi present in the environment have emerged as an increasingly common threat to human health. Cryptococcus neoformans and the closely related species Cryptococcus gattii are the leading causes of life-threatening fungal meningitis, and Australia is one of the few countries where both species are prevalent. Although C. neoformans is an increasingly common cause of infection in immunocompromised patients such as those suffering from AIDS, approximately one in four infected individuals has no apparent immune system defect. For patients with AIDS, in the absence of antiretroviral therapy cryptococcal infection is incurable and requires lifelong treatment with antifungal medication to keep the infection in check. During infection, Cryptococcus is under tremendous stress enforced not only by the immune system and the presence of antifungals, but also by the high temperature, nutrient limiting environment encountered in the host. The proposed research will reveal how Cryptococcus evolves in this environment to enable persistence of infection despite medical intervention. I propose that naturally occurring mobile genetic elements present in the Cryptococcus genome cause chromosomal rearrangements during long term infection to produce gene deletions and duplications that facilitate survival. By characterising these changes and the genes associated with them, the research will identify novel genes involved in pathogenesis and will increase our understanding of the infection process. The expected outcome of this project is a detailed understanding of the roles mobile element movement and chromosomal rearrangement play in Cryptococcus during infection, and how these affect genes that contribute to the pathogenic process. The fundamental knowledge gained from this study will facilitate studies designed to combat infections in the clinical setting, provide new drug targets and help foster the development of more effective therapies.Read moreRead less
Determinants Of Immune Restoration Disease And Persistent Immune Dysfunction In HIV Patients Responding To ART
Funder
National Health and Medical Research Council
Funding Amount
$445,011.00
Summary
Many people throughout the world now receive antiretroviral treatment (ART) for HIV-AIDS. ART increases numbers of CD4 T-cells, but does not restore all functions the immune system. In addition, some patients experience serious exacerbations of pre-existing secondary infections when they respond to ART. We were the first to describe these Immune Restoration Diseases and will investigate the underlying mechanisms and the causes of persistent immune deficiency here.
Envelope Glycoprotein Determinants Of Pathogenic, Macrophage-tropic HIV-1 And Their Role In HIV-1 Disease Progression
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Human immunodeficiency virus type 1 (HIV-1) causes AIDS and, to date, has infected 20 thousand people in Australia and 40 million worldwide. In addition to T-cells of the immune system, HIV-1 can also infect cells of the monocyte-macrophage lineage found in blood, brain, lymph node, lungs, bone marrow, skin and brain. HIV-1 strains that can infect these cells are called macrophage-tropic (M-tropic) strains. Infected macrophages are a major source of new HIV-1 produced in the body, and they compl ....Human immunodeficiency virus type 1 (HIV-1) causes AIDS and, to date, has infected 20 thousand people in Australia and 40 million worldwide. In addition to T-cells of the immune system, HIV-1 can also infect cells of the monocyte-macrophage lineage found in blood, brain, lymph node, lungs, bone marrow, skin and brain. HIV-1 strains that can infect these cells are called macrophage-tropic (M-tropic) strains. Infected macrophages are a major source of new HIV-1 produced in the body, and they complicate therapy by the current drugs used to treat HIV-1 infection because infection is often latent (or dormant) and, unlike T-cells, they are long lived and may continue to produce new virus for the duration of their normal life span. HIV-1 virus from patients with advanced disease (i.e. AIDS) can infect macrophages better than virus from patients at early stages of disease (i.e. just after infection, or during the asymptomatic or healthy period). Therefore, the increased ability of HIV-1 to infect macrophages, i.e., enhanced M-tropism, is an important factor contributing to the development of AIDS in people with HIV-1 infection. However, what causes HIV-1 to increase it's ability to infect macrophages and cause AIDS is unknown. This proposal aims to identify features of HIV-1 that are important for enhanced M-tropism and HIV-1 disease progression. We expect to find that the virus gradually changes during the course of infection to forms that can bind to receptor molecules on the cell more tightly, and to forms that need fewer receptors on the cell surface for infection. We believe that these forms of HIV-1 virus are now better able to infect macrophages, which naturally only have small amounts of receptors on their surface, and also can infect and kill T-cells better, leading to AIDS. This study will contribute to a greater understanding of how HIV-1 causes AIDS, which is necessary for the development of new drugs to treat HIV-1 infection.Read moreRead less
CD4+ T-cells In HIV - Regulator Or Target Of Viral Infection: A Modelling Approach
Funder
National Health and Medical Research Council
Funding Amount
$319,740.00
Summary
T-cell loss due to HIV infection causes immunodeficiency. Since virus grows faster if more T-cells are available and preferentially infects dividing cells, we want to understand how replacement, division and death of uninfected T-cells affect the progress of HIV infection and T-cell recovery during drug therapy. The results of our study will lead to a better understanding of HIV disease, and may assist in the development of novel treatment regimes optimising T-cell numbers during infection.