Investigating the early post-entry steps of the retrovirus life cycle. (360G-Wellcome-084955_Z_08_Z)

This research aims to define the poorly understood early post-entry stages of the retroviral lifecycle, in the hope that this will lead to new antiretroviral drug targets, improved gene therapy vectors, and better animal models for HIV/AIDS. Mutagenesis studies have implicated the viral capsid and p12 proteins in the trafficking of MLV particles. Viruses with specific mutations in either of these proteins are unable to accrue their DNA in the cell nucleus. Using a variety of virological assa ys I will determine the function of these proteins and assess whether p12 recruits a cellular factor required for replication, or if p12 blocks a cellular inhibitor of infection. I will also compare the roles of MLV and HIV capsids in viral trafficking. In addition, I will investigate cellular restriction factors that block early post-entry events. I will study the restriction of a novel human gamma-retrovirus, XMRV, recently isolated from prostate cancer patients. Comparing the restriction o f XMRV with other retroviruses will help to define the specificity and mechanism of restriction. Finally, I will identify novel cellular proteins involved in early post-entry processes by analysing the protein complexes of TAP-tagged p12 and Fv1 proteins, and studying the effects of RNaseH on retroviral infection.