Viral silencing and immune evasion pathways (360G-Wellcome-210688_Z_18_Z)

Studying how viruses manipulate their host cell machinery provides insight into both viral function and cellular regulation. Invasion by viral DNA threatens cellular integrity and therefore needs to be detected and suppressed. As the default cellular response is to silence incoming DNA, how do viruses subvert and exploit this hostile environment to their advantage? Our identification of the ‘Human Silencing Hub’ (HUSH) as a novel epigenetic transcriptional repressor complex, responsible for silencing newly integrated retroviruses, has motivated us to further investigate chromatin regulation of viral infection. We wish to: (i) Understand how HUSH silences newly integrated viral DNA. (ii) Determine how lentiviruses antagonize chromatin-mediated repression and identify shared mechanisms by which unrelated, non-integrated viruses counteract silencing. (iii) Understand how and why the lentiviral-Vif accessory protein manipulates the host cell phosphoproteome. To help address these questions we have developed and optimised powerful genetic and proteomic screening technologies. Repurposing CRISPR-Cas9 will enable RNA-guided genome manipulations, including selection of informative point mutants and isolation of DNA sequence-specific regulatory proteins. Together these approaches provide a discovery platform to determine how repressive heterochromatin is established and maintained, how viruses manipulate their chromatin environment and ultimately to develop new therapeutic tools to enable their eradication.