Noncanonical P gene mRNA editing in Cedar virus generates a V-like protein that is required for efficient virion production

Abstract

Highly pathogenic Hendra and Nipah viruses encode accessory P gene products (C, V and W) that antagonize innate immunity and contribute to pathogenicity. Cedar virus (CedV), an apathogenic bat-borne henipavirus, is presumed to lack P gene mRNA editing and therefore is unable to express V and W proteins. Here, we identify CedV peptides originating from a frameshifted P gene open reading frame and demonstrate a previously unrecognized, noncanonical editing site at a homopolymeric adenine tract that introduces single-nucleotide A or G insertion. This mRNA editing produces a protein that we refer to as U protein, whose C-terminal domain shares sequence and predicted structural features with those of the henipavirus V protein. Recombinant CedV mutants defective in mRNA editing were only recoverable by trans-complementation and showed markedly reduced release of infectious virus in cell culture and attenuated replication in mice lacking type I interferon receptor. Our data revise the CedV gene expression models and reveal a noncanonical editing mechanism that supports the production of a U protein critical for efficient infectious virus release. These results expand the fundamental concepts of paramyxovirus gene expression and reveal an unexpected requirement for P-gene editing in efficient infectious-virus production, with implications for the evaluation of potentially high-consequence paramyxoviruses.