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
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.
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
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
The Role Of HIV Infection Of Astrocytes In The Development Of HIV Associated Dementia
Funder
National Health and Medical Research Council
Funding Amount
$144,250.00
Summary
Dementia is an extremely common problem in the late stages of Human Immunodeficiency Virus (HIV) infection. HIV-associated dementia is the most common cause of dementia in people under 40 years of age. Despite the development of very good drugs to attack the virus, HIV-associaed dementia continues to be a major clinical problem. We are looking at the reasons why some people infected with HIV become demented and others do not. We are also looking at how best to prevent the development of dementia ....Dementia is an extremely common problem in the late stages of Human Immunodeficiency Virus (HIV) infection. HIV-associated dementia is the most common cause of dementia in people under 40 years of age. Despite the development of very good drugs to attack the virus, HIV-associaed dementia continues to be a major clinical problem. We are looking at the reasons why some people infected with HIV become demented and others do not. We are also looking at how best to prevent the development of dementia. We believe that astrocytes (an important brain cell that supports neurons) play a very important role in the development of HIV-associated dementia. With an improved understanding of the steps leading to dementia we can better plan treatments to prevent the development of this devastating complication of HIV-AIDS.Read moreRead less