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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
HIV-1 infection is characterised by high levels of virus replication and a progressive loss of immune cells, particularly CD4+ T lymphocytes. Highly active antiretrovial therapy (HAART) for HIV-1 infection results in profound suppression of viral replication, a substantial increase in CD4+ T lymphocytes and a decrease in morbidity and mortality. The primary source of T lymphocytes in early human development is the thymus. Recently, it has been demonstrated that the thymus remains functional thro ....HIV-1 infection is characterised by high levels of virus replication and a progressive loss of immune cells, particularly CD4+ T lymphocytes. Highly active antiretrovial therapy (HAART) for HIV-1 infection results in profound suppression of viral replication, a substantial increase in CD4+ T lymphocytes and a decrease in morbidity and mortality. The primary source of T lymphocytes in early human development is the thymus. Recently, it has been demonstrated that the thymus remains functional throughout adult life. The role of the thymus in HIV-1 infection remains controversial. Studies of the role of the thymus in HIV-1-infected individuals has been limited by the lack of a marker of thymic function in vivo. We have recently developed a novel assay to quantify cells of recent thymic origin by taking advantage of certain molecular events that occur in the thymus during the production of new T lymphocytes. This molecular event creates a circular piece of DNA, called a T-cell receptor excision circles (TREC). TREC concentration in the periphery will increase with an increase in thymic output but will reduce in the presence of T cell proliferation or cell death. In order to determine the contribution of the thymus to immune reconstitution following HAART, we plan to study the dynamics of thymus function in HIV-1 infection by measuring TREC and T cell turnover in HIV-1 infection prior to and following HAART. In a subgroup of individuals, more commonly seen following treatment of HIV-1 infection in children, there is an increase in CD4+ T lymphocytes in the absence of a significant reduction in viral suppression. The role of the thymus in this unique subset of individuals will be studied.Read moreRead less
Characterisation Of Polymorphism In HIV-1 Sequence: Investigation Of Viral Escape From HLA-restricted Immune Responses
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
Although drug therapy has been developed for treatment of HIV infection, there are many aspects of optimal long-term therapy that are problematic. An important reason for this is that HIV disease is different in different individuals, and we believe this is in large part attributable to the way in which the virus can escape an individual's unique immune responses against it. HIV has been shown to escape by mutating and evolving during infection, but the nature and extent to which this occurs in ....Although drug therapy has been developed for treatment of HIV infection, there are many aspects of optimal long-term therapy that are problematic. An important reason for this is that HIV disease is different in different individuals, and we believe this is in large part attributable to the way in which the virus can escape an individual's unique immune responses against it. HIV has been shown to escape by mutating and evolving during infection, but the nature and extent to which this occurs in everyone is not established. This is an important barrier to the design of effective vaccines against HIV. This study uses a novel method to describe the ways that HIV evolves uniquely in every individual, and to determine how this information relates to subsequent disease severity, response to therapy and response to vaccination. This will allow HIV infected patients to have better 'individualised' therapy as well as help in the design of effective vaccines.Read moreRead less
I am a virologist carrying out research to determine the mechanisms underlying rotavirus cellular tropism and the pathogenesis of rotavirus disease. Rotavirus is the major cause of infantile gastroenteritis worldwide. I am combining the expertise of my group in rotavirus biology with the power of inter-disciplinary collaborations in the areas of sugar chemistry, cell biology, structural biology and diabetes to expand understanding in these areas. Novel treatments and improvements in rotavirus va ....I am a virologist carrying out research to determine the mechanisms underlying rotavirus cellular tropism and the pathogenesis of rotavirus disease. Rotavirus is the major cause of infantile gastroenteritis worldwide. I am combining the expertise of my group in rotavirus biology with the power of inter-disciplinary collaborations in the areas of sugar chemistry, cell biology, structural biology and diabetes to expand understanding in these areas. Novel treatments and improvements in rotavirus vaccines are the long term goal of our research.Read moreRead less
Resolving Human Immunodeficiency Virus (HIV) Transmission
Funder
National Health and Medical Research Council
Funding Amount
$745,213.00
Summary
To increase the breadth of HIV prevention strategies, it is imperative that we biologically understand how HIV enters our bodies. Through two unique clinical cohorts, we will determine why circumcision is protective and how a commonly acquired sexual transmitted infection (human papilloma virus) can increase HIV transmission.
The Human Immunodeficiency Virus (HIV) is a virus that infects and kills the cells of your immune system. This infection eventually leads to the Acquired Immune Deficiency Syndrome (AIDS). An important aspect in preventing infection is to study how HIV enters immune cells and how infection spreads. Our lab is researching drugs to block the entry of HIV in immune cells, which can hopefully be used together with existing anti-HIV drugs to slow down the spread of the virus and the onset of AIDS.
Modulation Of Type 1 Diabetes Development By Rotavirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$413,775.00
Summary
Rotavirus is the main cause of severe diarrhoea in children, and may contribute to progression to type 1 diabetes. We have now shown that rotavirus also modulates diabetes in mice, by a novel mechanism. In this project, the mechanism of this process will be elucidated and the capacity of human rotavirus to affect diabetes will be determined. This study will help determine the design of further human studies, and whether rotavirus vaccines also are possible modulators of diabetes development.
Understanding The Establishment Of HIV Reservoirs And Development Of HIV Eradication Strategies
Funder
National Health and Medical Research Council
Funding Amount
$380,891.00
Summary
Understanding why, when, how and at what pace the HIV virus hides and establishes itself in one's body will allow us to design new ways for preventing and eliminating this reservoir of hidden HIV. As a clinician scientist in HIV and infectious diseases, I will drive clinical studies to explore the kinetics of HIV in patients who recently acquired HIV, those who start HIV treatment early, and those chronically infected with HIV so as to investigate novel means to minimise HIV hiding spots.