The ability of RNA viruses to rapidly mutate and develop resistance to medical countermeasures is a considerable barrier to the development of broadly acting antivirals. Viral genotyping can help determine the mechanistic basis and degree of barrier to the development of antiviral resistance. Core D will provide accurate, timely, and reproducible viral whole genome sequencing data for all Projects in this proposal. Using a combination of different sequencing approaches including metagenomic, hybridization capture, and amplicon tiling combined with a clinical trials-grade quality management infrastructure, Core D has built a robust and automated wet-lab and dry-lab pipeline for the recovery of RNA virus genomes. With the proposal’s focus on developing and characterizing broadly acting RNA polymerase-directed antivirals against a variety of RNA viruses, the Core D can simultaneously offer information on the mechanisms of resistance and activity of these antivirals using sequencing data as a readout. Specifically, we will recover viral whole genomes from viral isolates subjected to selection with the proposed antiviral compounds during in vitro and in vivo experiments to determine mechanisms of resistance and activity. In addition, the Genomics Core will enhance rigor, reproducibility, and generalizability of the proposed studies by ensuring the integrity of viral isolates and constructs prior to laborious and expensive in vivo experimentation in all Projects. The Core ensures that the Scientific Projects can obtain accurate results from high-throughput genomics testing without redundant effort to enable scientific inquiry into the activity of antivirals against a variety of high consequence RNA viruses.
