Exploring virus release as a bottleneck for the spread of influenza A virus infection in vitro and the implications for antiviral therapy with neuraminidase inhibitors

PLoS One. 2017 Aug 24;12(8):e0183621. doi: 10.1371/journal.pone.0183621. eCollection 2017.

Abstract

Mathematical models (MMs) have been used to study the kinetics of influenza A virus infections under antiviral therapy, and to characterize the efficacy of antivirals such as neuraminidase inhibitors (NAIs). NAIs prevent viral neuraminidase from cleaving sialic acid receptors that bind virus progeny to the surface of infected cells, thereby inhibiting their release, suppressing infection spread. When used to study treatment with NAIs, MMs represent viral release implicitly as part of viral replication. Consequently, NAIs in such MMs do not act specifically and exclusively on virus release. We compared a MM with an explicit representation of viral release (i.e., distinct from virus production) to a simple MM without explicit release, and investigated whether parameter estimation and the estimation of NAI efficacy were affected by the use of a simple MM. Since the release rate of influenza A virus is not well-known, a broad range of release rates were considered. If the virus release rate is greater than ∼0.1 h-1, the simple MM provides accurate estimates of infection parameters, but underestimates NAI efficacy, which could lead to underdosing and the emergence of NAI resistance. In contrast, when release is slower than ∼0.1 h-1, the simple MM accurately estimates NAI efficacy, but it can significantly overestimate the infectious lifespan (i.e., the time a cell remains infectious and producing free virus), and it will significantly underestimate the total virus yield and thus the likelihood of resistance emergence. We discuss the properties of, and a possible lower bound for, the influenza A virus release rate.

MeSH terms

  • Antiviral Agents / therapeutic use*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • In Vitro Techniques
  • Influenza A virus / isolation & purification*
  • Influenza, Human / drug therapy
  • Influenza, Human / transmission*
  • Neuraminidase / antagonists & inhibitors*

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Neuraminidase

Grants and funding

This work was supported in part by Discovery Grant 355837-2013 from the Natural Sciences and Engineering Research Council of Canada (www.nserc-crsng.gc.ca), and by Early Researcher Award ER13-09-040 from the Ministry of Research and Innovation and Science of the Government of Ontario (www.ontario.ca/page/early-researcher-awards), both awarded to CAAB, and by the Interdisciplinary Theoretical and Mathematical Sciences (iTHES, ithes.riken.jp; iTHEMS, ithems.riken.jp) research programmes at RIKEN (CAAB). Additional support in the form of an Ontario Graduate Scholarship from the Government of Ontario (www.osap.gov.on.ca) (LEL), a Michael Smith Foreign Study Supplement and a Doctoral Canadian Graduate Scholarship (CGS-D) from the Natural Sciences and Engineering Research Council of Canada (www.nserc-crsng.gc.ca) were awarded to LEL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.