Emergence of Fluoxetine-Resistant Variants during Treatment of Human Pancreatic Cell Cultures Persistently Infected with Coxsackievirus B4.

Enagnon Kazali Alidjinou,Ilka Engelmann,Antoine Bertin,Delphine Caloone,Didier Hober,Famara Sane

doi:10.3390/v11060486

Enagnon Kazali Alidjinou, Ilka Engelmann + Show 4 more

Open Access

https://doi.org/10.3390/v11060486

Copy DOI

Abstract

This study reports the antiviral activity of the drug fluoxetine against some enteroviruses (EV). We had previously established a model of persistent coxsackievirus B4 (CVB4) infection in pancreatic cell cultures and demonstrated that fluoxetine could clear the virus from these cultures. We further report the emergence of resistant variants during the treatment with fluoxetine in this model. Four independent persistent CVB4 infections in Panc-1 cells were treated with fluoxetine. The resistance to fluoxetine was investigated in an acute infection model. The 2C region, the putative target of fluoxetine antiviral activity, was sequenced. However, Fluoxetine treatment failed to clear CVB4 in two persistent infections. The resistance to fluoxetine was later confirmed in HEp-2 cells. The decrease in viral titer was significantly lower when cells were inoculated with the virus obtained from persistently infected cultures treated with fluoxetine than those from susceptible mock-treated cultures (0.6 log TCID50/mL versus 4.2 log TCID50/mL, p < 0.0001). Some previously described mutations and additional ones within the 2C protein were found in the fluoxetine-resistant isolates. The model of persistent infection is an interesting tool for assessing the emergence of variants resistant to anti-EV molecules. The resistance of EV strains to fluoxetine and its mechanisms require further investigation.

Highlights

The genus Enterovirus (Picornaviridae family) is a large group of small non-enveloped RNA viruses that are involved in several mild or severe acute clinical infections in humans ranging from enteric or respiratory infections, hand-foot-and-mouth disease, or conjunctivitis to acute flaccid paralysis, viral myocarditis, fulminant pancreatitis, or aseptic meningitis [1,2,3]
We further report the emergence of resistant coxsackievirus B4 (CVB4) variants during the fluoxetine-treatment of human pancreatic cell cultures persistently infected with the virus
Since the 2C viral protein was reported as the target of fluoxetine antiviral activity, we investigated whether the resistance was associated with mutant variants

Summary

Introduction

The genus Enterovirus (Picornaviridae family) is a large group of small non-enveloped RNA viruses that are involved in several mild or severe acute clinical infections in humans ranging from enteric or respiratory infections, hand-foot-and-mouth disease, or conjunctivitis to acute flaccid paralysis, viral myocarditis, fulminant pancreatitis, or aseptic meningitis [1,2,3]. Some of these viruses in this group, especially type B coxsackieviruses (CVB) are known to play a role in the development of chronic diseases, such as chronic myocarditis or type 1 diabetes [4,5,6]. The putative target of fluoxetine is Viruses 2019, 11, 486; doi:10.3390/v11060486 www.mdpi.com/journal/viruses

Methods

Results

Discussion

Conclusion