[Source: PLOS Pathogens, full page: (LINK). Abstract, edited.]
OPEN ACCESS / PEER-REVIEWED / RESEARCH ARTICLE
Influenza viruses that require 10 genomic segments as antiviral therapeutics
Alfred T. Harding , Griffin D. Haas , Benjamin S. Chambers, Nicholas S. Heaton
Published: November 15, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1008098 / This is an uncorrected proof.
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.
Influenza infections are best prevented via prophylactic vaccination. Vaccination, however, is incompletely efficacious, necessitating the use of anti-influenza therapeutics. To date, several different classes of anti-influenza therapeutics have been developed and used in order to combat these infections. Unfortunately, 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. Furthermore, given the manner in which they target influenza segment packaging, a conserved feature of all influenza A viruses, resistance to this therapeutic strategy is unlikely. Here, we report the development of a genetic platform that allows the production of replicating influenza viruses which require 10 genomic segments to be fully infectious. These viruses are capable of amplifying themselves in isolation, but coinfection with a wild-type virus leads to segment exchange and compromises the spread of both viruses. This interference, while mechanistically distinct from naturally occurring defective particles, was able to target the same viral process and rescue animals exposed to an otherwise lethal viral infection. This viral-based approach may represent a cost effective and scalable method to generate effective anti-influenza therapeutics when vaccines or antiviral drugs become ineffective due to the acquisition of viral resistance mutations.
Citation: Harding AT, Haas GD, Chambers BS, Heaton NS (2019) Influenza viruses that require 10 genomic segments as antiviral therapeutics. PLoS Pathog 15(11): e1008098. https://doi.org/10.1371/journal.ppat.1008098
Editor: Carolina B. Lopez, University of Pennsylvania, UNITED STATES
Received: February 7, 2019; Accepted: September 20, 2019; Published: November 15, 2019
Copyright: © 2019 Harding et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: N.S.H. is partially supported by federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under CEIRS Contract No. HHSN272201400005C. A.T.H and B.S.C. were supported by NIH training grant T32-CA009111. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Keywords: Influenza A.