Abstract
Influenza A viruses (IAVs) encode their genome across eight, negative sense RNA segments. During viral assembly, the failure to package all eight segments, or packaging a mutated segment, renders the resulting virion incompletely infectious. It is known that the accumulation of these defective particles can limit viral disease by interfering with the spread of fully infectious particles. In order to harness this phenomenon therapeutically, we defined which viral packaging signals were amenable to duplication and developed a viral genetic platform which produced replication competent IAVs that require up to two additional artificial genome segments for full infectivity. The modified and artificial genome segments propagated by this approach are capable of acting as “decoy” segments that, when packaged by coinfecting wild-type viruses, lead to the production of non-infectious viral particles. Although IAVs which require 10 genomic segments for full infectivity are able to replicate themselves and spread in vivo, their genomic modifications render them avirulent in mice. Administration of these viruses, both prophylactically and therapeutically, was able to rescue animals from a lethal influenza virus challenge. Together, our results show that replicating IAVs designed to propagate and spread defective genomic segments represent a potent anti-influenza biological therapy that can target the conserved process of particle assembly to limit viral disease.
Highlights
Influenza virus infections represent a substantial global burden on human health
The incidence of influenza resistance to many of these therapeutics has begun to rise, necessitating the development of new strategies. One such strategy is to mimic the activity of naturally occurring viral particles that harbor defective genomes. These defective interfering particles have the ability to interfere with productive viral assembly, preventing the spread of influenza viruses across the respiratory tract
We describe the genomic design of an Influenza A viruses (IAVs) strain that requires the presence of 10 genomic segments (10S virus) to be fully infectious that accomplishes this goal
Summary
Influenza virus infections represent a substantial global burden on human health. Each year, it is estimated that influenza viruses cause up to 5 million severe infections globally, resulting in up to 645,000 mortalities [1, 2]. Amantadines, which inhibit the influenza M2 ion channel were the first IAV therapeutics developed, and were approved for clinical use in 1966 [4]. Point mutations in the channel itself, can lead to resistance to these inhibitors, and high levels of resistance are widespread in H1, H3, H5, H7, H9, and H17 subtype influenza A viruses [5,6,7]. Neuraminidase inhibitors, such as oseltamivir, are the most commonly used IAV therapeutic [8]. One promising alternative therapeutic approach, that theoretically would be difficult for IAVs to develop resistance to, has been the utilization of defective viral particles that disrupt viral replication and packaging [14]
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