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Coinfection of semi-infectious particles can contribute substantially to influenza infection dynamics

Alex Farrell, Christopher Brooke, Katia Koelle, View ORCID ProfileRuian Ke
doi: https://doi.org/10.1101/547349
Alex Farrell
1Department of Mathematics, North Carolina State University, Raleigh, NC
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Christopher Brooke
2Department of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign
3Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, IL 61801
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Katia Koelle
4Department of Biology, Emory University, Atlanta, GA30322
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Ruian Ke
1Department of Mathematics, North Carolina State University, Raleigh, NC
5T-6, Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545
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  • ORCID record for Ruian Ke
  • For correspondence: rke@lanl.gov
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Abstract

Abstract Influenza is an RNA virus with a genome comprised of eight gene segments. Recent experiments show that the vast majority of virions fail to express one or more gene segments and thus cannot cause a productive infection on their own. These particles, called semi-infectious particles (SIPs), can induce virion production through complementation when multiple SIPs are present in an infected cell. Previous within-host influenza models ignore the potential effects of coinfection and SIPs during virus infection. Here, to investigate the extent that SIPs and coinfection impact viral dynamics, we constructed two within-host models that explicitly keep track of SIPs and coinfection, and fitted the models to clinical data published previously. We found that the model making a more realistic assumption that viruses can only reach a limited number of target cells allows for frequent co-infection during early viral exponential growth and predicts that SIPs contribute substantially to viral load. Furthermore, the model provides a new interpretation of the determinants of viral growth and predicts that the virus within-host growth rate (a measure of viral fitness) is relatively insensitive to the fraction of virions being SIPs, consistent with biological observations. Our results highlight the important role that cellular co-infection can play in regulating infection dynamics and provide a potential explanation for why SIP production is not highly deleterious. More broadly, the model can be used as a general framework to understand coinfection/superinfection in other viral infections.

Author Summary Influenza A viruses (IAVs) represent a large public health burden across the world. Currently, our understanding of their infection dynamics is incomplete, which hinders the development of effective vaccines and treatment strategies. Recently, it was shown that a large fraction of virions, called semi-infectious particles, do not cause productive infection on their own; however, coinfection of these particles leads to productive infection. The extent that semi-infectious particles and, more broadly, coinfection contribute to overall influenza infection dynamics is not clear. To address this question, we constructed mathematical models explicitly keeping track of semi-infectious particles and coinfection. We show that coinfection can be frequent over the course of infection and that SIPs play an important role in regulating infection dynamics. Our results have implications towards developing effective therapeutics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted February 12, 2019.
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Coinfection of semi-infectious particles can contribute substantially to influenza infection dynamics
Alex Farrell, Christopher Brooke, Katia Koelle, Ruian Ke
bioRxiv 547349; doi: https://doi.org/10.1101/547349
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Coinfection of semi-infectious particles can contribute substantially to influenza infection dynamics
Alex Farrell, Christopher Brooke, Katia Koelle, Ruian Ke
bioRxiv 547349; doi: https://doi.org/10.1101/547349

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