Modeling amantadine treatment of influenza A virus in vitro

Catherine A.A Beauchemin,James J Mcsharry,George L Drusano,Jack T Nguyen,Gregory T Went,Ruy M Ribeiro,Alan S Perelson

doi:10.1016/j.jtbi.2008.05.031

Abstract

We analyzed the dynamics of an influenza A/Albany/1/98 (H3N2) viral infection, using a set of mathematical models highlighting the differences between in vivo and in vitro infection. For example, we found that including virion loss due to cell entry was critical for the in vitro model but not for the in vivo model. Experiments were performed on influenza virus-infected MDCK cells in vitro inside a hollow-fiber (HF) system, which was used to continuously deliver the drug amantadine. The HF system captures the dynamics of an influenza infection, and is a controlled environment for producing experimental data which lend themselves well to mathematical modeling. The parameter estimates obtained from fitting our mathematical models to the HF experimental data are consistent with those obtained earlier for a primary infection in a human model. We found that influenza A/Albany/1/98 (H3N2) virions under normal experimental conditions at 37 ∘ C rapidly lose infectivity with a half-life of ∼ 6.6 ± 0.2 h , and that the lifespan of productively infected MDCK cells is ∼ 13 h . Finally, using our models we estimated that the maximum efficacy of amantadine in blocking viral infection is ∼ 74 % , and showed that this low maximum efficacy is likely due to the rapid development of drug resistance.

Highlights

Influenza A has become a growing concern for health authorities worldwide
Viral titer is determined from plaque assays, which yield the concentration of infectious virions
The loss of infectious virions can only come from the physical degradation of virion integrity, loss of virions through cell entry, or the loss of virion infectivity such that they no longer form plaques when used in plaque assays

Summary

Introduction

Influenza A has become a growing concern for health authorities worldwide. The annual cost of influenza illness and the threat of an imminent pandemic makes it all the more necessary to revisit the treatment options currently available. Resistance to adamantanes emerges rapidly during treatment and resistant variants show no evidence of fitness impairment and are readily transmissible (Deyde et al, 2007) This process, further amplified by the massive use of adamantanes, has led to widespread resistance among circulating influenza strains worldwide with 90.5% and 15.5% resistance prevalence among H3N2 and H1N1 strains, respectively (Deyde et al, 2007). The efficacy of combination therapy, including adamantanes and neuraminidase inhibitors, is an active subject of research (see Ilyushina et al, 2006; Gubareva et al, 2000). In these contexts, understanding the dynamics of adamantane treatment will be important to improve its effect

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Conclusion