Solving Delivery Of Gene Therapy For Control Of Human Immunodeficiency Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$765,439.00
Summary
Antiretroviral therapy free control of Human Immunodeficiency Virus (HIV) infection requires control of the viral reservoir. We have a unique approach, aimed at enforcing HIV latency by targeting highly conserved regions in the viral promoter. These constructs completely silence viral transcription for long periods of time. We intend to develop & assess vectors that are specifically targeted to the reservoir and which can enforce viral latency despite immune activation or viral variation.
HIV-1 Transcriptional Gene Silencing By Promoter Targeted Si/shRNAs: Uncovering Mechanisms, Optimising Delivery Systems, Assessing In Vivo Efficacy.
Funder
National Health and Medical Research Council
Funding Amount
$641,789.00
Summary
Current therapy for HIV is effective but must be taken for life. If therapy is stopped the virus comes back immediately from reservoirs not affected by current drugs. These fluctuating levels of virus are associated with increased illness and death. We are exploring a method of inducing prolonged viral latency using short double stranded RNA molecules. We propose to understand the mechanism of action of these possible therapeutics and to develop these constructs towards use in clinical trials.
A Potent Anti-HIV-1 Gene Therapy Agent In A Humanised Mouse Model
Funder
National Health and Medical Research Council
Funding Amount
$1,147,139.00
Summary
We have shown that a synthetic protein called Nullbasic can protect human cells from becoming infected by the AIDS virus, HIV-1. In this project a gene therapy approach will be used to test if a human immune system modified to contain Nullbasic is protected from HIV-1 in an animal model.
Current combination antiviral therapy can't cure an HIV infection because long-lived T-cells carrying latent HIV DNA can rekindle the infection when drugs are removed. We will study elements in HIV genetic code that control expression of HIV proteins from latent HIV. A detailed molecular understanding of the structure and function of these HIV RNA elements and the viral and host cell factors that interact with them will expose new targets for therapy of latent HIV.
Control Of Viral Replication By Non-coding Viral RNA
Funder
National Health and Medical Research Council
Funding Amount
$502,270.00
Summary
In 25 years since identified, HIV-AIDS deaths have exceeded 30 million and 40 million more are now living with HIV. The toll will soon far surpass any other infectious disease epidemic in history, or even military deaths from war in the past century. While effective combination drug therapies are available, multi-drug resistant HIV strains are commonly transmitted, leaving some patients with limited treatment options. New classes of drugs aimed at different steps in virus replication are urgentl ....In 25 years since identified, HIV-AIDS deaths have exceeded 30 million and 40 million more are now living with HIV. The toll will soon far surpass any other infectious disease epidemic in history, or even military deaths from war in the past century. While effective combination drug therapies are available, multi-drug resistant HIV strains are commonly transmitted, leaving some patients with limited treatment options. New classes of drugs aimed at different steps in virus replication are urgently needed. We have discovered that viral RNAs that do not code for protein serve important functions in HIV replication. We will study the molecular mechanisms these non-coding (intron) RNAs previously considered junk use to support of HIV gene expression and assess their potential as drug targets. First, we will investigate the role of these junk RNA loops, or lariat introns, produced in large amounts during the HIV replication cycle. Retroviruses employ RNA splicing to make mRNA for envelope and regulatory accessory genes. The complex alternative RNA splicing pattern of HIV spawns several non-coding lariats, including the lariat-intron that contains much of the removed env coding sequence. We have made the counterintuitive finding that the env-lariat dramatically enhances expression of Env protein. We will examine how this occurs and the involvement of the new class of gene-expression controlling micro-RNAs in this process. We will test for functional activity from the other lariat-introns that are produced by HIV. Second, we will characterise the mRNA-element required for efficient expression of the HIV envelope glycoprotein, Env gp160, which is essential for virus binding and entry during infection. This RNA-element directs the cell protein translation machinery to commence protein synthesis at the start of the Envgp160 rather than at upstream start sites for Vpu and Rev. We will determine how this RNA element works, its structure, and how it might be inactivated.Read moreRead less
Successful HIV remission and cure, where patients can live normally without daily drug therapy and risk of transmitting infectious virus, will critically depend on understanding the mechanisms that control the expression of viral messenger RNA and proteins. This project further explores the mechanisms controling poorly understood steps in the proecssing of viral mRNA that are required for HIV protein produciton, and identifies new targets and strategies to drive HIV into permanent remission.
The Pathogenesis And Prevention Of Congenital Cytomegalovirus Disease
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Cytomegalovirus (CMV) infection during pregnancy can have devastating effects on the developing baby, causing life-long disease and fetal death. Despite CMV being the most common infectious cause of fetal injury, there are significant gaps in our understanding of this congenital disease and no therapeutics available for use during pregnancy. This study will investigate the genetic molecular mechanisms by which CMV causes fetal injury and develop interventional therapies to reduce disease.
The Impact Of HIV Integration Sites On Eliminating HIV Latency
Funder
National Health and Medical Research Council
Funding Amount
$778,313.00
Summary
Current antiviral therapy for HIV controls virus production and allows recovery but does not eliminate the silent infection that prevents complete virus elimination and cure. We will examine two ways that HIV can silently infect T cells for differences in the sites at which the HIV DNA inserts into the genome. We will examine the way in which these differences at the genomic level may limit the ability to activate and eliminate persistent infection in memory T cells.
The Role Of Chemokine Signalling In Maintenance Of The Latent HIV Reservoir
Funder
National Health and Medical Research Council
Funding Amount
$92,161.00
Summary
HIV cure research aims to eliminate cells with HIV in their DNA. These cells have higher levels of a receptor, CCR6, signalling through which causes migration to and concentration in the gut. This gut migration may help to maintain the HIV reservoir by bringing susceptible cells close to infected cells. We will assess the effect of blocking CCR6 signalling on the ability to infect these cells with HIV in the laboratory and its effect on the reservoir of an analogous virus in macaques.
HIV Phenotypes Important For The Establishment Of Persistent Reservoirs In The Central Nervous System And Which Impact Neurotropism And Neuropathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$762,492.00
Summary
This grant will determine whether or not the CNS is a reservoir for HIV and identify the cellular targets of persistent infection and type of HIV-1 present.