Viral And Cellular Factors Affecting Early Steps In HIV Reverse Transcription
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
One of the key events in the life cycle of HIV is the conversion of viral RNA into a double stranded DNA intermediate. This process, called reverse transcription, is carried out by the viral enzyme reverse transcriptase (RT) in conjunction with other viral and cellular factors. While HIV RT has been extensively studied and RT inhibitors have been used in anti-retroviral therapy for HIV patients, other viral and cellular factors essential for efficient HIV reverse transcription have not been prop ....One of the key events in the life cycle of HIV is the conversion of viral RNA into a double stranded DNA intermediate. This process, called reverse transcription, is carried out by the viral enzyme reverse transcriptase (RT) in conjunction with other viral and cellular factors. While HIV RT has been extensively studied and RT inhibitors have been used in anti-retroviral therapy for HIV patients, other viral and cellular factors essential for efficient HIV reverse transcription have not been properly investigated and may represent a new class of anti-HIV targets.This project, based on our long standing (>10 years) research interest and experience, aims at identification of the viral and cellular factors particularly involved in the early steps of HIV reverse transcription.We have obtained preliminary data which lead to hypotheses regarding what kind of viral and cellular factors might be involved and their possible modes of action. Experiments have been designed to specifically prove or disprove these hypotheses. Thus this project will help us achieve a more comprehensive understanding on how HIV uses other viral and cellular factors, in addition to RT, to accomplish one of the mandatory stage of its growth (reverse transcription); and identify viral and cellular factors which can be further explored as new targets for anti-retroviral therapy. This is particularly important, as HIV resistance to current drug therapy has emerged as one serious issue facing HIV patients, and the HIV care communities.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
Modulation Of Cell Phospholipids And Membranes By 7-ketocholesterol And Their Role In Cholesterol Efflux.
Funder
National Health and Medical Research Council
Funding Amount
$186,372.00
Summary
Atherosclerosis is a leading cause of death in Australia. The disease is caused by the formation of large deposits of cholesterol in the walls of major blood vessels. This cholesterol comes from cholesterol-carrying particles in the blood which penetrate into the tissue of the blood vessel. They are taken up by the cells of the tissue which become engorged with large amounts of cholesterol and are called 'foam cells'. These foam cells also contain a small but signficant amount of damaged (oxidis ....Atherosclerosis is a leading cause of death in Australia. The disease is caused by the formation of large deposits of cholesterol in the walls of major blood vessels. This cholesterol comes from cholesterol-carrying particles in the blood which penetrate into the tissue of the blood vessel. They are taken up by the cells of the tissue which become engorged with large amounts of cholesterol and are called 'foam cells'. These foam cells also contain a small but signficant amount of damaged (oxidised) forms of cholesterol, called oxysterols. We have found than an oxysterol called 7-ketocholesterol makes it difficult for cells to get rid of excess cholesterol. Therefore this oxysterol may be part of the reason why foam cells develop. This project will study how 7-ketocholesterol blocks cholesterol removal from cells. This may lead to the development of drugs which remove or prevent 7-ketcholesterol accumulation in the blood vessel and so prevent or reverse atherosclerosis.Read moreRead less