- Viruses depend on host cellular machinery for entry, replication, assembly, and egress; targeting shared host dependencies may enable antivirals effective across multiple viral families.
- Historically, antiviral development focuses on virus-specific targets (e.g., viral enzymes), which are vulnerable to resistance and often lack cross-family breadth.
- Host-specific targets offer complementary countermeasures with a higher barrier to viral escape and potential broad-spectrum activity, but identifying robust host targets has been challenging.
- By integrating functional genomics data across multiple virus families of pandemic concern. This analysis uncovers host pathways repeatedly co-opted by unrelated viruses, strengthening confidence in their relevance as antiviral targets.
Key Findings: Brice et al. undertook a meta-analysis of 62 published functional genomics screens (e.g., CRISPR knockouts, RNAi, proteomics) of 10 virus families associated with pandemic risk (Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, Phenuiviridae, Picornaviridae, Poxviridae and Togaviridae.).1 Using robust rank aggregation (RRA) and protein–protein interaction network analyses, the authors identified conserved human cellular pathways required for viral replication across multiple viral families and mapped these pathways to candidate host-directed antiviral targets. Host factors included:
- Vacuolar (V-type) ATPase complex: These host factors are involved in endosomal acidification and membrane fusion and required for viral entry or intracellular trafficking.
- Glycosaminoglycan (GAG) synthesis: Genes involved in early GAG synthesis and heparin sulfate synthesis were identified. These host factors are required for viral attachment or co-receptor function, representing a shared early step in infection across diverse viruses.
- Golgi and vesicular trafficking: Components of the COPI coatomer and COG complex were identified, demonstrating a conserved requirement for intracellular transport and processing of viral components.
- Endoplasmic reticulum membrane protein insertion: A multi-subunit transmembrane complex that functions as an ER membrane insertase was identified, underscoring the ER’s role in viral protein biogenesis and assembly.
Bigger Picture: Viruses are obligate intracellular parasites that rely on host machinery in order to propagate. This comprehensive meta-analysis advances our understanding of the virus–host interface by pinpointing precise cellular processes consistently exploited by pandemic-relevant viruses to replicate. By aggregating evidence from multiple independent functional screens, it provides a higher-confidence map of conserved host dependencies than any single study could achieve. Confirmed host pathways such as glycosaminoglycan biosynthesis and V-ATPase function represent compelling targets for broad-spectrum, host-directed antiviral drug development, which may complement vaccines and direct-acting antivirals, especially for pathogens lacking effective vaccines. Validation of these pathways in physiologically relevant models and with existing small-molecule inhibitors could accelerate preparedness for future pandemics by diversifying antiviral response options.
(Image Credit: iStock/koto_feja)
References:
- Brice et al. 2026. Meta-Analysis of Functional Genomics Studies Reveals Conserved Cellular Pathways Required by Viruses of Pandemic Concern. Access Microbiology.
