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
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
Silent Mutations In The HIV-1 Reverse Transcriptase Selected During Antiretroviral Therapy
Funder
National Health and Medical Research Council
Funding Amount
$555,325.00
Summary
This project seeks to determine the role of silent mutations in the HIV reverse transcriptase that are selected during drug therapy in HIV infected individuals on HIV fitness, reverse transcriptase function and the emergence of drug resistance. This study will increase our understanding of the mechanisms by which the virus evades the effects of antiretrovirals and will provide a rationale for deciding on the best drug combinations for use in patients infected with specific HIV strains (clades).
Worldwide there are approximately 40 million people living with HIV-AIDS. An effective HIV vaccine does not exist at present. Therefore, current strategies to control the HIV pandemic include the use of life saving antiretroviral drugs. While the current drugs are successful in controlling infections, new and more effective agents are needed that inhibit HIV replication by distinct mechanisms due to the inevitable development of drug resistant strains of HIV. The HIV reverse transcriptase enzyme ....Worldwide there are approximately 40 million people living with HIV-AIDS. An effective HIV vaccine does not exist at present. Therefore, current strategies to control the HIV pandemic include the use of life saving antiretroviral drugs. While the current drugs are successful in controlling infections, new and more effective agents are needed that inhibit HIV replication by distinct mechanisms due to the inevitable development of drug resistant strains of HIV. The HIV reverse transcriptase enzyme is essential for HIV replication and has been a successful target for nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). NNRTIs act in part by stabilizing the reverse transcriptase enzyme, thus blocking enzyme function. However, no drugs have been developed that can specifically prevent formation of the reverse transcriptase enzyme, which would result in the production of noninfectious viral particles. We propose that formation of the active reverse transcriptase enzyme, from a large polyprotein called Gag-Pol, proceeds through a homodimer intermediate, which represents an ideal target for blocking reverse transcriptase formation in HIV infected cells. This homodimer intermediate is an attractive target with greater potential for disruption with small molecule inhibitors compared to the mature reverse transcriptase enzyme as it is less stable than the reverse transcriptase found in viruses. This study will determine whether formation of the active RT enzyme is dependent on this intermediate. In addition, we will examine how the reverse transcriptase encoded on Gag-Pol regulates activation of the HIV protease, which is also critical for the formation of infectious virus particles. These studies will increase our understanding of how the virus produces infectious particles and will identify new approaches for targeting the HIV reverse transcriptase enzyme.Read moreRead less
Molecular Studies Of The Astrocyte Reservoir Of HIV-1 In The Central Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$592,661.00
Summary
HIV infects the brain causing dementia in 10-20% patients. Strategies aimed at eradicating HIV infection fail to take into account CNS infection. Understanding the way in which HIV enters, infects and replicates in the brain is pivotal in development of drugs to prevent brain infection and dementia. Our studies have shown that HIV infection of the brain involves mechanisms distinct to those observed for blood and other organs. This study seeks to clarify such mechanisms.
Molecular Studies Of The Astrocyte Reservoir Of HIV-1 In The Central Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$533,828.00
Summary
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. HIV infects the central nervous system and causes HIV associated dementia in 10-20% of patients with AIDS. Despite the introduction of highly active antiretroviral therapy the prevalence in Australia continues to rise and studies have shown that the incidence has been under represented in the South east Asian region. Infection of the ....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. HIV infects the central nervous system and causes HIV associated dementia in 10-20% of patients with AIDS. Despite the introduction of highly active antiretroviral therapy the prevalence in Australia continues to rise and studies have shown that the incidence has been under represented in the South east Asian region. Infection of the CNS has two major implications for the treatment of AIDS patients. Firstly, HIV-associated dementia is the most common cause of dementia in people under 40 and this continuing increase in the number of young adults with dementia is placing increased pressure on health resources in the community. Secondly, strategies aimed at eradicating HIV infection from AIDS patients have thus far have failed to take into account the important and unique viral reservoir present in the CNS of an infected patient. The mechanisms involved in HIV-1infection of the brain remain unclear. Understanding the mechanisms by which HIV enters, infects and replicates the brain, are pivotal to the development of regimes to prevent infection of the brain in the first instance as well as development of targeted drug therapy to prevent dementia. Our preliminary studies have shown that HIV infection of the brain involves unique HIV virus and cellular mechanism distinct to those observed for the blood and other organs. This study seeks to clarify such mechanisms. This study will contribute to a greater understanding of how HIV-1 enters the brain and causes dementia, both of which are essential to the development of new drugs to treat HIV-1 infection.Read moreRead less
HIV is a rapidly evolving virus, and within an infected individual it continually acquires new mutations and joins together mutations by recombination. We have developed a novel system for studying recombination, and find that different individuals have different recombination rates, which may contribute to why some individuals survive longer. This project aims to identify the mechanisms responsible for differing recombination rates and how we can alter these to improve patient outcome.