Inhibition of herpes simplex virus reactivation by dipyridamole in a mouse model.
Herpes simplex virus (HSV) thymidine kinase (TK) has been demonstrated to be important for reactivation from latency. Specifically, HSV latency-associated transcripts (LAT) are expressed during latent infection established by TK-negative (TK-) HSV mutants, but reactivation is minimal. TK- HSV, however, readily reactivated in the presence of exogenous thymidine (TdR) in explant medium [Tenser et al. (1996): Journal of Virology 70:1271-1276]. In the present report this was further studied by evaluating the effect of dipyridamole (DPM) on HSV reactivation. DPM is known to interfere with nucleoside transport. Inhibition of TdR-enhanced reactivation of TK- HSV and inhibition of reactivation of wild-type TK+ HSV were evaluated in an experimental mouse model of latency. Without DPM, TK- HSV reactivation was increased from 0% to 88% with TdR in explant medium, demonstrating TdR-enhanced reactivation of TK- HSV (as seen previously), TdR-enhanced reactivation of TK- HSV was decreased when DPM (25 or 50 microM) was also present, to 30%-60% and to 0%, respectively. Secondly, DPM also decreased reactivation of wild-type TK+ HSV. The reactivation frequency of latently infected dorsal root ganglia was 90% in standard medium (no added TdR), and this was decreased by DPM to 9% and 0%, respectively. Reactivation of trigeminal ganglia in standard medium was 100%, and this decreased to 59% and 23%, respectively. The possibility of a direct toxic effect of DPM on ganglion neurons to explain the results was unlikely. DPM had a modest antiviral effect on HSV replication in cell culture, and its efficacy in blocking reactivation may be related to this activity, probably by inhibition of nucleoside transport.
Division of Neurology, Pennsylvania State University College of Medicine, Hershey, USA.
K A
KA
Hay
A
A
Gaydos
R B
RB
Tenser
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004176:Dipyridamole / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D013936:Thymidine / Q000494:pharmacology; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000821:virology; D014709:Vero Cells; D014775:Virus Activation / Q000187:drug effects*
D000998:Antiviral Agents; D004176:Dipyridamole; D013936:Thymidine