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
HIV infection is a dynamic process, in which the host immune response tries to control viral growth and keep up with the rapid evolution of the virus. This project assembles an interdisciplinary team of mathematicians and biologists to use a modelling approach to understand the dynamics of viral infection, viral evolution, and immune control in the infected individual. The insights gained from this project will help in the development of new drug and vaccination strategies.
The Role Of CXCR3 Chemokines In Hepatitis C And Other Forms Of Viral Hepatitis
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
The majority of individuals infected with hepatitis C virus (HCV) show a slow progression of liver disease over a period of 10-20 years. This liver disease is primarily a result of the host immune response to liver cells (hepatocytes) infected with HCV. As part of this immune response there in an increase in the number of immune cells that infiltrate the liver. To date we do not fully understand the mechanims that attract these cells to the liver but a class of molecules called chemokines is the ....The majority of individuals infected with hepatitis C virus (HCV) show a slow progression of liver disease over a period of 10-20 years. This liver disease is primarily a result of the host immune response to liver cells (hepatocytes) infected with HCV. As part of this immune response there in an increase in the number of immune cells that infiltrate the liver. To date we do not fully understand the mechanims that attract these cells to the liver but a class of molecules called chemokines is the most likely candidate. Thus a greater understanding of the chemokines expressed in the liver, their modulation and role in attracting immune cells to the liver in HCV-related liver disease will help us understand the basic mechanisms of liver disease with the possibility of development of novel therapeutic strategies. In pilot studies we have shown that the chemokine interferon-inducible T cell alpha chemoattractant (I-TAC) is significantly increased in the liver of persons infected with HCV. I-TAC is a member of the CXCR3 ligand chemokine family that attracts lymphocytes to sites of inflammation and as such may play an important role in hepatitis C. We have also shown that hepatocytes express I-TAC and that HCV can upregulate expression of I-TAC in a laboratory model of HCV replication. This proposal plans to determine the molecular mechanisms of I-TAC expression in response to HCV replication and to investigate if I-TAC expression is unique for hepatits C or a general feature of viral infections of the liver. We also plan to determine the the role of I-TAC and other CXCR3 ligand family members in a mouse model of viral hepatitis through the use of CXCR3 ligand antagonists. These experiments will enhance or knowledge of the role of the CXCR3 ligands in hepatitis C and viral hepatitis in general.Read moreRead less
Functions Of Viral Chemokine Receptor Homologues Important For Cytomegalovirus Pathogenesis And Latency
Funder
National Health and Medical Research Council
Funding Amount
$461,597.00
Summary
Cytomegalovirus (CMV) causes life-threatening disease in babies, transplant recipients and HIV-AIDS patients. We will focus on a CMV gene that has been 'hijacked' from the host cell and enables the virus to switch on signalling molecules within infected cells. We will determine how these signals enable CMV to infect sites of the body that are critical for virus transmission and contribute to long-term virus persistence. Our results will provide new strategies for drugs against CMV.
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.
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.
Understanding The Role Of Ongoing Viral Activity In Herpes Simplex Virus Latency
Funder
National Health and Medical Research Council
Funding Amount
$980,762.00
Summary
The virus that causes cold sores and genital herpes has a dormant phase from which renewed infection can recur. We recently discovered that this dormant phase is more active than we thought and we now want to learn how the body acts to suppress the virus so that these defence mechanisms might be improved to stop recurrent infections.
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.