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.
Hay
K A
KA
Division of Neurology, Pennsylvania State University College of Medicine, Hershey, USA.
Gaydos
A
A
Tenser
R B
RB
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