Interferon and Human Pandemic Viruses

We wish to define the key interferon (IFN)-stimulated gene (ISG) effectors for three pathogenic human viruses - HIV-1, SARS-CoV-2 and influenza virus - and understand the molecular basis for antiviral function. Specific ISGs will be identified in unbiased gene silencing (siRNA/ CRISPRi) screens, some of which we have developed. For HIV-1, we will initially focus on the antiviral mechanisms and post-transcriptional regulation of post-entry inhibitors we have identified, human-TRIM5alpha and MX2, including the central roles played by ubiquitination and phosphorylation. Our discovery that NCOA7 suppresses endocytic virus infection (e.g., SARS-CoV-2) provides the opportunity to study how the endolysosomal system can be dysregulated, potentially through altering vacuolar-ATPase activity. New screens for ISGs targeting SARS-CoV-2 or influenza virus will be undertaken using wild-type viruses as well as engineered strains carrying disruptions in candidate IFN- or ISG-antagonists. We will explore the molecular mechanisms and regulatory pathways used by the most potent ISGs using multiple complementary experimental approaches, including proteomic and approved drug screens, and determine how these viruses escape or survive ISG action. By understanding the ISG effectors that can control these viruses, we will gain fresh insights into viral replication strategies, disease processes and host immunity, and inform future antiviral therapeutic development.