Control of viral replication by non-coding viral RNA [ 2006 - 2008 ]

Research Grant

Researchers: Prof Damian Purcell (Principal investigator)

Brief description 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.

Funding Amount $AUD 502,270.54

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant