Neuronal activity regulates viral replication of herpes simplex virus type 1 in the nervous system.
Herpes simplex virus types 1 and 2 (HSV-1, -2) infect and also establish latency in neurons. In the present study, the authors investigated the influence of neuronal activity on the replication of HSV-1. The results showed that the sodium channel blocker tetrodotoxin (TTX) and the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) could significantly increase viral replication in primary neuronal cultures, by two- to fourfold. In contrast, KCl reduced viral production by at least 80% in the same cultures. Inhibitors of GABA(A) receptors completely abolished the effects of GABA. Intravitreously injected TTX in a mouse corneal scarification model enhanced the viral titers > 10-fold in both the trigeminal ganglia and the brain. At 2 h post infection, both TTX and GABA significantly up-regulated the levels of transcription for the viral immediate early (IE) genes ICP0, ICP4, and ICP27, as revealed by real time PCR. These results indicate that the neuronal excitation status may dictate the efficiency of HSV-1 viral replication, probably by regulating the levels of viral IE gene expression. These are the first findings connecting neuronal activity to the molecular mechanisms of HSV replication in the nervous system, which may significantly influence our view of herpesvirus infection and latency.
Zhang
Cheryl X
CX
Department of Surgery and Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Ofiyai
Harrison
H
He
Ming
M
Bu
Xuexian
X
Wen
Yanhua
Y
Jia
William
W
D000818:Animals; D001921:Brain / Q000821:virology; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006561:Herpes Simplex / Q000378:metabolism / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D007276:Injections, Intraventricular; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000187:drug effects / Q000821:virology*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D013779:Tetrodotoxin / Q000008:administration & dosage / Q000494:pharmacology; D014158:Transcription, Genetic; D012668:Trigeminal Ganglion / Q000378:metabolism / Q000821:virology; D044767:Ubiquitin-Protein Ligases; D014779:Virus Replication; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
C057120:ICP27 protein, human herpesvirus 1; D017874:Immediate-Early Proteins; C048925:herpes simplex virus, type 1 protein ICP4; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1