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 μM) 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.