A review of mathematical models of influenza A infections within a host or cell culture: lessons learned and challenges ahead

Beauchemin, C.; Handel, Andreas

doi:10.1186/1471-2458-11-s1-s7

Cited by 215 publications

(257 citation statements)

References 133 publications

(152 reference statements)

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“…This simple model and variants have been used in several recent analyses of influenza A virus within-host infection dynamics (e.g. [35,36] for reviews). The model tracks uninfected cells, U; infected cells, I; and free infectious virus, V. Cells become infected at rate k, infected cells produce virus at rate p and die at rate d. Free virus is cleared at rate d. The equations for uninfected cells, infected cells and free virus are given by dU/dt ¼ 2kUV, dI/dt ¼ 2kUV2dI and dV/dt ¼ pI2dV.…”

Section: Materials and Methods (A) Experimental Datamentioning

confidence: 99%

Trade-offs between and within scales: environmental persistence and within-host fitness of avian influenza viruses

et al. 2014

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Trade-offs between different components of a pathogen's replication and transmission cycle are thought to be common. A number of studies have identified trade-offs that emerge across scales, reflecting the tension between strategies that optimize within-host proliferation and large-scale population spread. Most of these studies are theoretical in nature, with direct experimental tests of such cross-scale trade-offs still rare. Here, we report an analysis of avian influenza A viruses across scales, focusing on the phenotype of temperaturedependent viral persistence. Taking advantage of a unique dataset that reports both environmental virus decay rates and strain-specific viral kinetics from duck challenge experiments, we show that the temperature-dependent environmental decay rate of a strain does not impact within-host virus load. Hence, for this phenotype, the scales of within-host infection dynamics and between-host environmental persistence do not seem to interact: viral fitness may be optimized on each scale without cross-scale trade-offs. Instead, we confirm the existence of a temperature-dependent persistence trade-off on a single scale, with some strains favouring environmental persistence in water at low temperatures while others reduce sensitivity to increasing temperatures. We show that this temperature-dependent trade-off is a robust phenomenon and does not depend on the details of data analysis. Our findings suggest that viruses might employ different environmental persistence strategies, which facilitates the coexistence of diverse strains in ecological niches. We conclude that a better understanding of the transmission and evolutionary dynamics of influenza A viruses probably requires empirical information regarding both within-host dynamics and environmental traits, integrated within a combined ecological and within-host framework.

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Section: Materials and Methods (A) Experimental Datamentioning

confidence: 99%

Trade-offs between and within scales: environmental persistence and within-host fitness of avian influenza viruses

et al. 2014

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“…The influenza model by Baccam et al (6) is the most parsimonious in vivo viral dynamics model reported and is based on the fundamental predator-prey concept: a pool of free virus infecting a susceptible pool of target respiratory epithelial cells. It is similar to the earlier models used to describe human immunodeficiency virus dynamics (7), but differs in that no turnover is assumed for the target cells because the duration of acute influenza virus infection (approximately 7 days) is much shorter than the life span of the target respiratory epithelial cells, an assumption which does not hold true for chronic infections such as AIDS or hepatitis C (7)(8)(9).…”

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confidence: 99%

A Drug-Disease Model Describing the Effect of Oseltamivir Neuraminidase Inhibition on Influenza Virus Progression

Kamal

Gieschke

Lemenuel‐Diot

et al. 2015

Antimicrob Agents Chemother

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A population drug-disease model was developed to describe the time course of influenza virus with and without oseltamivir treatment and to investigate opportunities for antiviral combination therapy. Data included viral titers from 208 subjects, across 4 studies, receiving placebo and oseltamivir at 20 to 200 mg twice daily for 5 days. A 3-compartment mathematical model, comprising target cells infected at rate ␤, free virus produced at rate p and cleared at rate c, and infected cells cleared at rate ␦, was implemented in NONMEM with an inhibitory Hill function on virus production (p), accounting for the oseltamivir effect. In congruence with clinical data, the model predicts that the standard 75-mg regimen initiated 2 days after infection decreased viral shedding duration by 1.5 days versus placebo; the 150-mg regimen decreased shedding by an additional average 0.25 day. The model also predicts that initiation of oseltamivir sooner postinfection, specifically at day 0.5 or 1, results in proportionally greater decreases in viral shedding duration of 5 and 3.5 days, respectively. Furthermore, the model suggests that combining oseltamivir (acting to subdue virus production rate) with an antiviral whose activity decreases viral infectivity (␤) results in a moderate additive effect dependent on therapy initiation time. In contrast, the combination of oseltamivir with an antiviral whose activity increases viral clearance (c) shows significant additive effects independent of therapy initiation time. The utility of the model for investigating the pharmacodynamic effects of novel antivirals alone or in combination on emergent influenza virus strains warrants further investigation. O seltamivir is an orally active antiviral which inhibits the neuraminidase enzyme necessary for the release of newly replicated influenza virus from infected cells. Oseltamivir has a wide spectrum of activity, acting against a range of influenza A and B subtypes. The Centers for Disease Control and Prevention reported that 99.6% of the 2009 H1N1 viral strains tested were susceptible to oseltamivir (see http://www.cdc.gov/H1N1flu /recommendations.htm). The standard regimen of 75 mg twice a day (b.i.d.) for 5 days is used for treatment of seasonal influenza as previous studies in adult subjects showed that this regimen results in plasma levels sufficient to inhibit neuraminidase enzyme activity from all the tested seasonal influenza virus strains (1, 2). The same treatment regimen was applied in the most recent H1N1 pandemic in 2009-2010 without a prospective dose optimization trial, due to the impracticality of performing such a study on an emergent viral strain during a pandemic. The World Health Organization has recommended use of higher doses (150-mg regimen) for treatment of highly virulent strains such as H5N1 (3). In addition, there were reported concerns regarding the ability of oseltamivir manufacturing capacity to fully meet global stockpiling demands if a rapid pandemic ensues (4, 5). This factor, in addition to opportunities for enh...

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“…Thus, mathematical modeling has been used to capture the dynamics of influenza virus infection and to understand the interaction of the virus with the immune system (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). Much of the work has been focused on the basic relationship between the host and the virus (25,26,32,34,35), whereas other work has strived to quantify the interplay between viral replication and adaptive immunity (27)(28)(29)(30)36).…”

mentioning

confidence: 99%

Effects of Aging on Influenza Virus Infection Dynamics

Hernandez‐Vargas

Wilk

Canini

et al. 2014

J Virol

127

119

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The consequences of influenza virus infection are generally more severe in individuals over 65 years of age (the elderly). Immunosenescence enhances the susceptibility to viral infections and renders vaccination less effective. Understanding age-related changes in the immune system is crucial in order to design prophylactic and immunomodulatory strategies to reduce morbidity and mortality in the elderly. Here, we propose different mathematical models to provide a quantitative understanding of the immune strategies in the course of influenza virus infection using experimental data from young and aged mice. Simulation results suggested a central role of CD8 ؉ T cells for adequate viral clearance kinetics in young and aged mice. Adding the removal of infected cells by natural killer cells did not improve the model fit in either young or aged animals. We separately examined the infection-resistant state of cells promoted by the cytokines alpha/beta interferon (IFN-␣/␤), IFN-␥, and tumor necrosis factor alpha (TNF-␣). The combination of activated CD8؉ T cells with any of the cytokines provided the best fits in young and aged animals. During the first 3 days after infection, the basic reproductive number for aged mice was 1.5-fold lower than that for young mice (P < 0.05). IMPORTANCEThe fits of our models to the experimental data suggest that the increased levels of IFN-␣/␤, IFN-␥, and TNF-␣ (the "inflammaging" state) promote slower viral growth in aged mice, which consequently limits the stimulation of immune cells and contributes to the reported impaired responses in the elderly. A quantitative understanding of influenza virus pathogenesis and its shift in the elderly is the key contribution of this work.

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A review of mathematical models of influenza A infections within a host or cell culture: lessons learned and challenges ahead

Cited by 215 publications

References 133 publications

Trade-offs between and within scales: environmental persistence and within-host fitness of avian influenza viruses

Trade-offs between and within scales: environmental persistence and within-host fitness of avian influenza viruses

A Drug-Disease Model Describing the Effect of Oseltamivir Neuraminidase Inhibition on Influenza Virus Progression

Effects of Aging on Influenza Virus Infection Dynamics

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