Cyclic nucleotide modulation of herpes simplex virus latency and reactivation

Clinical observations and experimental studies suggested that the relative proportions of ganglionic neuronal intracellular cyclic adenosine monophosphate (c-AMP) and cyclic guanosine monophosphate (c-GMP) concentrations may influence the state or activity of herpes simplex viral DNA in its relationship with the host cell DNA. We studied the effects of putative modulators of intracellular cyclic nucleotide levels on herpes simplex virus (HSV) reactivation from latency in murine trigeminal ganglion cells. We also investigated the effects of these same mediators on the c-GMP and/or c-AMP concentrations in HSV-latently infected trigeminal ganglion cells and in acyclovir-suppressed, HSV-infected neuroblastoma cells. Cholera toxin and theophylline increased c-AMP levels (2-fold and 5-fold at 1 min and 30 sec, respectively for cholera toxin and 2-fold and 1.5-fold at 1 min and 30 sec for theophylline) and enhanced the rapidity of HSV reactivation from latency (P less than 0.005). Exogenous dibutyryl c-AMP also stimulated viral reactivation (P less than 0.005). Carbamylcholine increased c-GMP levels (7-fold and 6-fold at 15 sec and 30 sec, respectively), produced no significant change in c-AMP levels, and delayed HSV reactivation from latency (P less than 0.005). None of these mediators had a demonstrable effect on HSV replication.