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.
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
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
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
The HIV-1 Spacer Peptide P1: A Novel Anti-retroviral Target
Funder
National Health and Medical Research Council
Funding Amount
$384,000.00
Summary
Human immunodeficiency virus type 1 (HIV-1) is the virus that causes AIDS. The treatment that is in current use, called highly active anti-retroviral therapy (HAART), has significantly delayed the onset of AIDS in HIV-1 infected patients. This therapeutic regimen requires the action of three or more drugs to generate a potency that is sufficient to suppress the virus and restrict outgrowth of resistant mutants. However, even on HAART the virus continues to replicate at a low level, and the threa ....Human immunodeficiency virus type 1 (HIV-1) is the virus that causes AIDS. The treatment that is in current use, called highly active anti-retroviral therapy (HAART), has significantly delayed the onset of AIDS in HIV-1 infected patients. This therapeutic regimen requires the action of three or more drugs to generate a potency that is sufficient to suppress the virus and restrict outgrowth of resistant mutants. However, even on HAART the virus continues to replicate at a low level, and the threat of the development of resistant mutations is ever present. Consequently, additional drug targets are required to continue the successful treatment of HIV-1 infected patients. This research is focused on a large polyprotein produced by HIV called Gag. One end of Gag contains a smaller protein called P1 that is crucial for the ability of HIV to reproduce itself. Small changes to the genetic makeup of P1 (one or two amino acids) lead to a defective virus that cannot replicate. The apparent integral role of P1 in viral replication makes it an excellent target for anti-retroviral therapy. With this project we will further our understanding of P1's role in HIV replication and look at ways we target P1 for the development of effective anti-viral agents.Read moreRead less
Extraction Of Key Features Of Natural Speech By Ventral Cochlear Nucleus Neurons
Funder
National Health and Medical Research Council
Funding Amount
$225,330.00
Summary
Little is known about how speech is processed and transformed by the central auditory pathway, and how the critical temporal and spectral features that identify a speech sound segment (a phoneme) are extracted. To date, most studies have approached this issue by using synthetic speech and examined the responses of the peripheral auditory nerve only. The aim of this study is to examine how important features of naturally-spoken speech are encoded by the cochlear nucleus (CN) - the first station i ....Little is known about how speech is processed and transformed by the central auditory pathway, and how the critical temporal and spectral features that identify a speech sound segment (a phoneme) are extracted. To date, most studies have approached this issue by using synthetic speech and examined the responses of the peripheral auditory nerve only. The aim of this study is to examine how important features of naturally-spoken speech are encoded by the cochlear nucleus (CN) - the first station in the auditory pathway located in the brainstem. The CN is a complex of different cell types that have the capacity to transmit, transform, and encode complex acoustic information in different ways. The proposed experiments involve recording the bioelectrical signal from single CN cells in anaesthetised rats while presenting naturally-spoken syllables, both in quiet and in the presence of noise. It is important to examine what happens to the neural responses in the latter condition, because all animals must cope with the problem of extracting important signals from background noise. While noise clearly interferes with the perception of another sound, the auditory system is in fact quite good at extracting signals in the presence of noise. This is well demonstrated by our ability to understand speech in the presence of quite high noise levels. This ability is severely degraded in the hearing impaired. Thus, one of the aims of this study is to examine the mechanisms and limits of the CN's ability to encode speech in a noisy background. A greater understanding of the mechanisms the nervous system uses to extract critical features of speech will not only build on our knowledge of auditory brainstem processes, but may also provide clues to improving processing strategies for cochlear implants.Read moreRead less
Modelling The Interaction Between Sexually Transmitted Infections And HIV Transmission To Inform Public Health Policy
Funder
National Health and Medical Research Council
Funding Amount
$543,624.00
Summary
Other sexually transmitted infections (STIs) increase the risk of acquiring or transmitting HIV. Using mathematical models the population level effects of this increased risk will be investigated. This work will inform the design of effective and efficient STI treatment programs that aim to reduce the number of HIV infections in Australian gay men, prevent HIV epidemics in Aboriginal and Torres Strait Island communities, and slow the growth of HIV in Papua New Guinea.
Human immunodeficiency virus type 1 (HIV-1) causes AIDS and, to date, has infected approximately 20 thousand people in Australia and more than 40 million worldwide. People infected with HIV-1 first experience a period of 5-7 years where they remain healthy, ofter assisted by the use of anti-HIV-1 drugs, and this period is referred to as the asymptomatic period. After this period, infected individuals become sick due to their immune system being destroyed, and this is referred to as AIDS. Researc ....Human immunodeficiency virus type 1 (HIV-1) causes AIDS and, to date, has infected approximately 20 thousand people in Australia and more than 40 million worldwide. People infected with HIV-1 first experience a period of 5-7 years where they remain healthy, ofter assisted by the use of anti-HIV-1 drugs, and this period is referred to as the asymptomatic period. After this period, infected individuals become sick due to their immune system being destroyed, and this is referred to as AIDS. Research into how HIV-1 causes AIDS has shown us that the virus changes over time to make itself better able to kill cells of the immune system, by at least 2 mechanisms. The first mechanism, which is the best characterised one, is where the virus changes the way it infects cells, whereby it can infect many more cells in the body by taking advantage of an alternate receptor molecule on the cell called CXCR4. This molecule is very widely expressed on immune cells, and thus the virus can now infect and kill many more cells. However, in about 50% of infected people who eventually get AIDS, the virus does not change this way. The virus instead uses it's original receptor to infect cells, called CCR5. Our preliminary studies, as well as other published reports, suggest that the virus changes itself another way to make it kill immune cells better, without using CXCR4. However, the mechanism by which HIV-1 does this is poorly understood. This proposal aims to better understand this mechanism. We expect to find that, in this group of patients, the Env proteins on the virus change to be able to bind CCR5 more tightly, and thus be able to use fewer molecules of CCR5 to infect cells. We believe that these forms of the virus are now better able to kill immune cells, 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