Apoptosis by influenza viruses correlates with efficiency of viral mRNA synthesis

Abstract

A mutant influenza virus, A/NWS-Mvi, grows well in the presence of exogenous sialidase activity sufficient to remove all cell surface sialic acids. Related wild-type viruses grow very poorly under these conditions, although mutant and wild-type viruses bind to desialylated cells with similar efficiency and show similar reduction of binding to sialidase-treated cells compared to native cells. Here we examine entry, transcription, translation, and RNA replication and find that, although the viruses appear to utilize the same entry pathway, the mutant NWS-Mvi transcribes and replicates RNA to higher levels than the wild-type strains. The kinetics of replication in multi-cycle infection show that this enhancement of RNA synthesis facilitates growth where entry is restricted. The hemagglutinin (HA) protein of NWS-Mvi lyses red blood cells 0.1 pH unit higher than wild-type viruses. This higher fusion pH may allow more efficient release of nucleocapsids from endosomes and contribute to the enhanced RNA synthesis. The efficient RNA synthesis assists virus survival at low inocula or under stringent growth conditions, such as the presence of antiviral agents. NWS-Mvi induces apoptosis in infected cells more readily than wild-type viruses, apparently as a consequence of enhanced production of viral mRNA. Since growth of NWS-Mvi is more efficient, apoptosis may play a positive role in viral replication by removing cells that have already been infected from those capable of making more virus.