Modeling amantadine treatment of influenza A virus in vitro.
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 degrees C rapidly lose infectivity with a half-life of approximately 6.6+/-0.2 h, and that the lifespan of productively infected MDCK cells is approximately 13 h. Finally, using our models we estimated that the maximum efficacy of amantadine in blocking viral infection is approximately 74%, and showed that this low maximum efficacy is likely due to the rapid development of drug resistance.
Beauchemin
Catherine A A
CA
Department of Physics, Ryerson University, 350 Victoria St., Toronto, ON M5B2K3, Canada. cbeau@ryerson.ca
McSharry
James J
JJ
Drusano
George L
GL
Nguyen
Jack T
JT
Went
Gregory T
GT
Ribeiro
Ruy M
RM
Perelson
Alan S
AS
D000547:Amantadine / Q000627:therapeutic use*; D000818:Animals; D016923:Cell Death; D002460:Cell Line; D004285:Dogs; D024882:Drug Resistance, Viral; D053122:Influenza A Virus, H3N2 Subtype; D053124:Influenza A Virus, H5N1 Subtype; D009980:Influenza A virus; D007668:Kidney / Q000821:virology*; D008954:Models, Biological; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000821:virology; D013997:Time Factors; D014771:Virion; D014773:Virology / Q000295:instrumentation / Q000379:methods; D014774:Virulence
D000547:Amantadine