The diversity of HIV quasispecies within a single AIDS patient is far greater than the global diversity of influeneza annually, highlighting the enormous burden HIV imposes on the immune network. The capacity of HIV-1 to evolve quickly has significantly impaired our effort to produce effective vaccine and long lasting treatment strategy. This project utilizes multidisciplinary approaches to delineate determinants that drives the diversification of HIV-1.
Elucidation Of Immune Mechanisms Underlying HSV Vaccine Development
Funder
National Health and Medical Research Council
Funding Amount
$573,993.00
Summary
HSV-1 and -2 causes genital herpes, cold sores, encephalitis, potential fatal neonatal herpes, keratitis and blindness as well as severe disease in transplant patients. HSV infection also enhances the acquisition of HIV by 2-3 fold. Investigating the mechanism of immune response to HSV infection or components of HSV will assist in understanding immune control of HSV, HSV vaccine development, and assist in reducing in HIV spread.
Transposable Element Mobility And Chromosomal Rearrangement In The Fungal Pathogen Cryptococcus During Human Infection
Funder
National Health and Medical Research Council
Funding Amount
$322,028.00
Summary
Pathogenic fungi present in the environment have emerged as an increasingly common threat to human health. Cryptococcus neoformans and the closely related species Cryptococcus gattii are the leading causes of life-threatening fungal meningitis, and Australia is one of the few countries where both species are prevalent. Although C. neoformans is an increasingly common cause of infection in immunocompromised patients such as those suffering from AIDS, approximately one in four infected individuals ....Pathogenic fungi present in the environment have emerged as an increasingly common threat to human health. Cryptococcus neoformans and the closely related species Cryptococcus gattii are the leading causes of life-threatening fungal meningitis, and Australia is one of the few countries where both species are prevalent. Although C. neoformans is an increasingly common cause of infection in immunocompromised patients such as those suffering from AIDS, approximately one in four infected individuals has no apparent immune system defect. For patients with AIDS, in the absence of antiretroviral therapy cryptococcal infection is incurable and requires lifelong treatment with antifungal medication to keep the infection in check. During infection, Cryptococcus is under tremendous stress enforced not only by the immune system and the presence of antifungals, but also by the high temperature, nutrient limiting environment encountered in the host. The proposed research will reveal how Cryptococcus evolves in this environment to enable persistence of infection despite medical intervention. I propose that naturally occurring mobile genetic elements present in the Cryptococcus genome cause chromosomal rearrangements during long term infection to produce gene deletions and duplications that facilitate survival. By characterising these changes and the genes associated with them, the research will identify novel genes involved in pathogenesis and will increase our understanding of the infection process. The expected outcome of this project is a detailed understanding of the roles mobile element movement and chromosomal rearrangement play in Cryptococcus during infection, and how these affect genes that contribute to the pathogenic process. The fundamental knowledge gained from this study will facilitate studies designed to combat infections in the clinical setting, provide new drug targets and help foster the development of more effective therapies.Read moreRead less
Application Of Protein Microarrays To Develop A Cross-Species Malaria Vaccine
Funder
National Health and Medical Research Council
Funding Amount
$451,821.00
Summary
Malaria remains a significant public health problem worldwide. Five species of malaria parasites infect humans. The ideal vaccine would be effective against all five species. Using a novel protein microarray approach, we will identify Plasmodium proteins that may be excellent targets of a cross-species malaria vaccine. This research will build on Australia's current strengths in biotechnology and will result in significant economic benefits by facilitating the development of a malaria vaccine.
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
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
SERPINB2 IS AN INDUCIBLE HOST FACTOR INVOLVED IN ENHANCING HIV-1 TRANSCRIPTION AND REPLICATION
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
SerpinB2 is one of the most abundant proteins made at sites of inflammation. We have shown that HIV-1 infection also induces SerpinB2 and that SerpinB2 then helps the virus to replicate. In this grant we seek to understand how the virus causes this protein to be made and how this protein then increases virus replication. In the human population there are different forms of SerpinB2 and this grant seeks to determine whether these different forms affect HIV-1 replications differently. It may for i ....SerpinB2 is one of the most abundant proteins made at sites of inflammation. We have shown that HIV-1 infection also induces SerpinB2 and that SerpinB2 then helps the virus to replicate. In this grant we seek to understand how the virus causes this protein to be made and how this protein then increases virus replication. In the human population there are different forms of SerpinB2 and this grant seeks to determine whether these different forms affect HIV-1 replications differently. It may for instance be possible that an individual who has a certain form of SerpinB2 may be less susceptable to AIDS following HIV-1 infection.Read moreRead less
Inhibition Of Nef-activated Src-family Kinases By CHK
Funder
National Health and Medical Research Council
Funding Amount
$514,307.00
Summary
HIV hijacks infected blood cells to produce its own proteins. Nef is one of these proteins and Nef alone is sufficient to cause an AIDS-like disease. Recently, we discovered that a protein called CHK can inhibit Nef. Our research will determine how CHK inhibits Nef and test the feasibility of drugs based on CHK. Such drugs would slow AIDS progression, assisting conventional therapies and patients' immune systems to combat the infection, leading to longer, healthier, more productive lives.