Activation of second-messenger pathways reactivates latent herpes simplex virus in neuronal cultures.
Herpes simplex virus type 1 (HSV-1) establishes latent infections in neurons of sympathetic and sensory ganglia in humans, and reactivation of latent virus results in recurrent disease. Previously, we reported establishment of latent HSV-1 infections in neuronal cultures derived from rats, monkeys, and humans; reactivation occurs following nerve growth factor (NGF) deprivation. The processes controlling HSV latency are not understood. Using the in vitro neuronal latency system, we have shown that latent HSV-1 reactivated in response to stimulation of at least two second-messenger pathways. Stimulation of cAMP-dependent pathways by several mechanisms or activation of protein kinase C by phorbol myristate acetate (PMA) resulted in reactivation of latent HSV-1. The reactivation kinetics following treatment with activators of protein kinase A and C were accelerated compared with those following NGF deprivation. 2-Aminopurine, which inhibits NGF-stimulated protein kinases and other classes of protein kinases, but does not effect protein kinase A or C, blocked reactivation produced by NGF deprivation or treatment with a cAMP analog, but not reactivation by PMA treatment. These results demonstrate that latent HSV-1 reactivates in neurons in vitro in response to activation of second-messenger pathways.
Smith
R L
RL
University of Colorado Health Sciences Center, Department of Neurology, Denver 80262.
Pizer
L I
LI
Johnson
E M
EM
Wilcox
C L
CL
D002460:Cell Line; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007700:Kinetics; D009414:Nerve Growth Factors / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000382:microbiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D015290:Second Messenger Systems; D018139:Simplexvirus / Q000254:growth & development* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013873:Thionucleotides / Q000378:metabolism; D014775:Virus Activation
D009414:Nerve Growth Factors; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000242:Cyclic AMP; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate