Antiviral activity of WIN 54954 in coxsackievirus B2 carrier state infected human myocardial fibroblasts.
Persistent infections with a cardiotropic enterovirus, e.g. coxsackievirus B2 (CVB2), cause chronic myocarditis and eventually congestive heart failure. Therefore, the antiviral activity of WIN 54954, a capsid binding antiviral agent that inhibits enterovirus uncoating, was studied in persistently CVB2-infected cultures of human myocardial fibroblasts. Cultures displayed a typical carrier state infection with virus titers of 3.9 +/- 1.6 x 10(5) plaque forming units (PFU)/ml and 0.99% infected cells. WIN 54954 (0.025-1 microg/ml) application was started 7 days after infection of the cultures. Compared to the WIN 54954 concentration resulting in a 90% plaque number reduction (EC90 = 0.197 microg/ml) in acutely infected Vero cells, WIN 54954 reduced virus yields of myocardial fibroblast cultures more efficiently, e.g. more than 100 fold (99%) with 0.025 microg/ml after 4 days of application. Antiviral effects of WIN 54954 increased with application time and at 0.025 microg/ml Win 54954 completely inhibited infectious virus progeny after 16 days. Increasing the WIN 54954 concentration up to 1 microg/ml did not cause a greater inhibition of virus replication. In situ hybridization demonstrated that at 0.1 microg/ml WIN 54954 reduced the number of infected cells from 0.99 to 0.18%, although a complete eradication of CVB2-infected cells was not achieved at concentrations as high as 1 microg/ml. In conclusion, the results indicate that low concentrations of WIN 54954 are effective in treating persistent enterovirus infections of myocardial fibroblasts, although a complete eradication of the infection is not achieved with WIN 54954 as a single antiviral agent.
Heim
A
A
Institut für Virologie und Seuchenhygiene, Medizinische Hochschule Hannover, Germany. ahei@virolgie.mh-hannover.de
Pfetzing
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U
Müller
G
G
Grumbach
I M
IM
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002353:Carrier State / Q000188:drug therapy* / Q000821:virology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003384:Coxsackievirus Infections / Q000188:drug therapy* / Q000821:virology; D004305:Dose-Response Relationship, Drug; D029822:Enterovirus B, Human / Q000187:drug effects* / Q000502:physiology; D005347:Fibroblasts / Q000821:virology; D006321:Heart / Q000821:virology*; D006801:Humans; D017403:In Situ Hybridization; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012194:RNA-Directed DNA Polymerase; D014709:Vero Cells; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D007555:Isoxazoles; C062554:Win 54954; D012194:RNA-Directed DNA Polymerase