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.
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
Escape And Reversion Of Critical Immune Responses: Insights Into Effective Immunity To HIV
Funder
National Health and Medical Research Council
Funding Amount
$372,446.00
Summary
The HIV pandemic is a global emergency. The overall goal of this grant proposal is to elucidate the requirements for protective immunity to HIV. Although immune responses have some effect on HIV replication, the virus mutates and evolves to escape immune pressure. However, each mutation away from wild-type virus likely results in at least some impairment in the ability of the virus to replicate. Where efficient immune responses target regions of the virus that are critical to virus replication, ....The HIV pandemic is a global emergency. The overall goal of this grant proposal is to elucidate the requirements for protective immunity to HIV. Although immune responses have some effect on HIV replication, the virus mutates and evolves to escape immune pressure. However, each mutation away from wild-type virus likely results in at least some impairment in the ability of the virus to replicate. Where efficient immune responses target regions of the virus that are critical to virus replication, escape mutations may result in viral variants incapable of causing disease. Resulting from an exciting collaboration between HIV and theoretical biologists, we have recently identified techniques to calculate the effectiveness of immunity and the cost of subsequent immune escape variants. We will use and expand these techniques to identify immune responses that result in the most effective control of viral replication. These studies will lead to ways to improve HIV vaccines and thereby prevent HIV.Read moreRead less
Mechanisms Underlying APOBEC3G Restriction Of HIV-1
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
In the fight against worldwide HIV-AIDS, understanding natural cell defenses to the HIV virus may identify new virus targets and strategies to block HIV in humans. Here, we will use state-of-the-art, high resolution, fluorescent microscopy to understand how the recently identified cell protein, APOBEC3G, blocks the HIV life cycle in human cells. We anticipate that APOBEC3G will stop HIV from invading the nucleus of human cells to defend against HIV, a strategy we can apply to new therapies.
The HIV-1 Tat Protein Is An Reverse Transcription Co-factor.
Funder
National Health and Medical Research Council
Funding Amount
$404,592.00
Summary
HIV-1 is the virus that causes AIDS. In order for HIV-1 to grow, the viral genetic material must be converted into a form that is compatible with a human host. Specifically, the HIV-1 genetic material is made of RNA while the human genome is composed of DNA. An HIV-1 enzyme called reverse transcriptase (RT) is used for this purpose. We have discovered that another HIV-1 protein called Tat is also required for the efficient conversion of HIV-1 RNA into HIV-1 DNA. If HIV-1 lacks Tat, then this tra ....HIV-1 is the virus that causes AIDS. In order for HIV-1 to grow, the viral genetic material must be converted into a form that is compatible with a human host. Specifically, the HIV-1 genetic material is made of RNA while the human genome is composed of DNA. An HIV-1 enzyme called reverse transcriptase (RT) is used for this purpose. We have discovered that another HIV-1 protein called Tat is also required for the efficient conversion of HIV-1 RNA into HIV-1 DNA. If HIV-1 lacks Tat, then this transformation process is inefficient and HIV-1 is not able to grow. Recently our group made a breakthrough discovery on how Tat works. Tat can directly bind to RT and stimulate the conversion process. This research is aimed at a detailed analysis of Tat and RT interaction. This information is required in order to understand how this interaction can be blocked in order to stop HIV-1 growth. In the long-term, results produced by this research will be required to discover novel drugs to combat HIV-AIDS.Read moreRead less