Valproic acid interferes with antiviral treatment in human cytomegalovirus-infected endothelial cells.
OBJECTIVE
The endothelium represents a natural site of human cytomegalovirus (HCMV) infection involved in viral spreading and persistence. Moreover, HCMV infection of endothelial cells has been associated with different pathological conditions of the cardiovascular system. Here, the influence of the antiepileptic drug valproic acid (VPA) was investigated on HCMV replication in human umbilical vein endothelial cells alone or in combination with the antiviral drugs ganciclovir, cidofovir or foscarnet.


RESULTS
HCMV replication was observed by immunostaining for viral antigens and by virus yield assay. Protein expression and phosphorylation were examined by western blot. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye reduction assay. Therapeutic VPA concentrations (< or =1 mM) increased HCMV immediate early antigen, late antigen, and viral titres of different endotheliotropic and non-endotheliotropic HCMV strains in a concentration- and time-dependent manner up to 30-fold. Moreover, VPA impaired the antiviral activity of the anti-HCMV drugs ganciclovir, cidofovir, and foscarnet. VPA inhibits histone deacetylases (HDAC) and induces HDAC-independently extracellular signal-regulated kinases 1/2 (ERK 1/2) phosphorylation in endothelial cells. Both effects observed, HCMV stimulation and interference with antiviral drugs, depend on HDAC inhibition but not on ERK 1/2 phosphorylation.


CONCLUSIONS
These findings suggest to carefully monitor the frequency of HCMV reactivation in cardiovascular patients treated with VPA (or other HDAC inhibitors) in comparison to control individuals.
Michaelis
Martin
M
Institut für Medizinische Virologie, Klinikum der JW Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
Ha
T Anh T
TA
Doerr
Hans Wilhelm
HW
Cinatl
Jindrich
J
D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D004347:Drug Interactions; D042783:Endothelial Cells / Q000821:virology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D010766:Phosphorylation; D014635:Valproic Acid / Q000494:pharmacology*; D014775:Virus Activation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D048049:Extracellular Signal-Regulated MAP Kinases