Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development

YB (Yuebang) Yin, Yongyi Wang, Wen Dang, L (Lei) Xu, JH Su, XY Zhou, Wenshi Wang, K Felczak, Luc van der Laan, KW Pankiewicz, Annemiek Baltissen - van der Eijk, Marcel Bijvelds, Dave Sprengers, Hugo de Jonge, Marion Koopmans, Herold Metselaar, Maikel Peppelenbosch, Qiuwei Pan

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Rotavirus infection has emerged as an important cause of complications in organ transplantation recipients. Immunosuppressants used to prevent alloreactivity can also interfere with virus infection, but the direct effects of the specific type of immunosuppressants on rotavirus infection are still unclear. Here we profiled the effects of different immunosuppressants on rotavirus using a 2D culture model of Caco2 human intestinal cell line and a 3D model of human primary intestinal organoids inoculated with laboratory and patient-derived rotavirus strains. We found that the responsiveness of rotavirus to Cyclosporine A treatment was moderate and strictly regulated in an opposite direction by its cellular targets cyclophilin A and B. Treatment with mycophenolic acid (MPA) resulted in a 99% inhibition of viral RNA production at the clinically relevant concentration (10 mu g/ml) in Caco2 cells. This effect was further confirmed in organoids. Importantly, continuous treatment with MPA for 30 passages did not attenuate its antiviral potency, indicating a high barrier to drug resistance development. Mechanistically, the antiviral effects of MPA act via inhibiting the IMPDH enzyme and resulting in guanosine nucleotide depletion. Thus for transplantation patients at risk for rotavirus infection, the choice of MPA as an immunosuppressive agent appears rational. (C) 2016 Elsevier B.V. All rights reserved.
Original languageUndefined/Unknown
Pages (from-to)41-49
Number of pages9
JournalAntiviral Research
Publication statusPublished - 2016

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