Mechanistic insights into Nipah virus 5' UTR functionality reveal an antiviral target.

Abstract

The highly pathogenic Nipah virus (NiV), a World Health Organization priority pathogen with pandemic potential, remains a critical public health threat due to its capacity to cause fatal encephalitis and respiratory disease. Despite its 1998 emergence, no approved therapeutics exist against NiV infection, underscoring the urgent need to identify genomic regulatory elements as antiviral targets. Our study focuses on the extended 5' UTRs characteristic of NiV transcripts, a distinctive genomic feature whose functional significance remained enigmatic. Comparative reporter assays showed these UTRs strongly inhibit downstream ORF translation through mechanisms distinct from internal ribosome entry site activity. Mutagenesis studies identified upstream ATG elements in multiple transcripts as critical regulators of translational efficiency, with the C 5' UTR exhibiting maximal suppression. A functional hotspot spanning within the C 5' UTR was mapped as the primary ribosomal initiation blockade, and ribosome leaky scanning was confirmed as the mechanism enabling dual-protein expression. Notably, therapeutic targeting of this regulatory element with antisense oligonucleotides significantly impaired viral replication. These findings provide fundamental insights into henipaviral translation regulation while identifying concrete antiviral targets, particularly the druggable C 5' UTR element, advancing efforts to combat this biosafety level 4 pathogen.