Nature Communications· 2026Q1
Coevolutionary constraints of Zika virus nonstructural protein 5 replication and interferon antagonism activities
- 3citations
- Q1SCImago
- 2026year
Short summary
Zika virus NS5 protein's replication and interferon antagonism functions are tightly linked, with no single mutation allowing for loss of antagonism without impairing replication.
AI-generated from the title and abstract; the full text is not read.
Key points
- Zika virus NS5 protein's RNA replication and interferon antagonism functions are genetically linked.
- Extensive overlap exists between the amino acid determinants for replication and STAT2 antagonism.
- No single mutation was found to eliminate antagonism without impairing replication.
- Combinations of mutations allowed for reduced antagonism while preserving replication, leading to attenuated viruses in mice.
AI-generated from the title and abstract; the full text is not read.
Abstract
The flavivirus nonstructural protein 5 performs multiple functions during infection, including RNA replication and type I interferon signaling antagonism. Although flavivirus NS5 proteins inhibit IFN signaling through distinct mechanisms, which suggests evolutionary flexibility, the evolutionary constraints for these activities to coexist within a single protein remain to be determined. Here, we mapped the Zika virus NS5 STAT2 antagonism determinants and compared them with replication constraints defined by deep mutational scanning. Antagonism and replication determinant extensively overlapped, and no single amino acid substitution eliminated antagonism without impairing replication. Resolving these fitness landscapes in parallel identified specific combinations of partially functional substitutions that retained replication capacity while markedly reducing antagonism. These viruses were profoundly attenuated in human STAT2 knock-in mice. Our results uncover a fundamental evolutionary constraint linking replication and immune evasion activities in NS5, highlight that STAT2 antagonism is essential for ZIKV pathogenesis and provide new avenues for attenuated ZIKV vaccines.
The authors' abstract, as published at the source. Nature Communications, 2026 · DOI ↗
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Field: Public Health, Environmental and Occupational Health
Public Health, Environmental and Occupational HealthMedicine