From CRISPR functional genomics to synthetic interventions: engineering antiviral strategies

ABSTRACT Virus-host interactions govern infection outcomes and viral evolution, but host determinants that enable or restrict viral replication have been difficult to map comprehensively and in the right cellular contexts. Pooled CRISPR perturbation screens now provide scalable, mechanistic entry points into host dependency and restriction landscapes across diverse viruses. Recent extensions, including single-cell readouts, imaging and spatial phenotyping, organoid models, and in vivo selection, are shifting the field from static hit lists toward contextual maps that explain how host pathways and cell states shape permissiveness. In parallel, synthetic biology is translating these maps into programmable intervention classes, including receptor decoys and binders that intercept entry, conditional protein depletion systems that modulate host factors with temporal control, gene circuits that couple infection sensing to tailored responses, and engineered immune cells with tunable antiviral functions. This review highlights conceptual and technical advances that connect CRISPR functional genomics to synthetic antiviral design, summarizes emerging principles that generalize across viral families, and discusses constraints that will determine whether screen-nominated mechanisms can be engineered into effective and safe antiviral strategies.