Understanding host interactions with retroelements using Ty3 as a model system

描述（由申请人提供）：

DESCRIPTION (provided by applicant): Retroviruses are agents of disease in humans and animals, but they also hold the potential to be the vehicles of gene therapy. Retroviruses are RNA viruses that infect a cell, reverse transcribe their RNA into DNA and then integrate their viral DNA into the host genome at which point they are free to replicate and produce more viral particles for further infection. Sixteen million people have died worldwide from AIDS, the causative agent being the HIV retrovirus, and another 50 million people are infected worldwide. All viruses are absolutely dependent on host factors for their proliferation. Understanding which factors are absolutely essential for viral replication could lead the way to developing new therapeutic agents to combat viral infections. The goal of this project is to use yeast and the retrotransposon Ty3 as a model system to identify host functions that affect the retrotansposon lifecycle and potentially the retrovirus lifecycle. Ty3 resembles retroviruses in its genome organization and the proteins encoded. The retrotransposon lifecycle has parallels with the intracellular retroviral lifecycle and differs mainly in that it does not have an extracellular phase. First we are taking advantage of similarities between Ty3 and retroviruses to understand host cell cycle inhibition of reverse transcriptase activity. Reverse transcriptase is one of the most commonly targeted enzymes of anti-retroviral drugs so understanding cell cycle regulation of RT activity could potentially uncover new ways to target and restrict retroviral infection. Second we are characterizing the possible requirements of host S phase checkpoint activation in Ty3 replication. Finally we have used bioinformatics approaches to identify murine homologs of yeast genes known to affect the Ty3 lifecycle. We propose to test the effect these genes have on retroviral replication. Since the retrotransposon and retroviral lifecycles are similar and because of the high degree of conservation between yeast and mammalian genes, this approach may uncover a way to rapidly identity novel cellular factors required for retroviral replication. There are two major ways in which this study could impact public health. Our work may identify host factors in mammalian cells that are important for viral replication and this knowledge could aid in the development of new anti-viral therapeutics. This is an important issue for public health as there are resistant strains of HIV to almost all known drugs. Also our study could provide information crucial in the development of retroviruses for use as vectors to deliver gene therapy treatments by addressing the issues of viral integration into the host cell.