The HSV-1 ICP4 Transcriptional Auto-Repression Circuit Functions as a Transcriptional "Accelerator" Circuit

Front Cell Infect Microbiol. 2020 Jun 24;10:265. doi: 10.3389/fcimb.2020.00265. eCollection 2020.


Herpes simplex virus-1 (HSV-1) is a significant human pathogen. Upon infection, HSV-1 expresses its immediate early (IE) genes, and the IE transcription factor ICP4 (infectious cell protein-4) plays a pivotal role in initiating the downstream gene-expression cascade. Using live-cell time-lapse fluorescence microscopy, flow cytometry, qPCR, and chromatin immunoprecipitation, we quantitatively monitored the expression of ICP4 in individual cells after infection. We find that extrinsic stimuli can accelerate ICP4 kinetics without increasing ICP4 protein or mRNA levels. The accelerated ICP4 kinetics-despite unchanged steady-state ICP4 protein or mRNA level-correlate with increased HSV-1 replicative fitness. Hence, the kinetics of ICP4 functionally mirror the kinetics of the human herpesvirus cytomegalovirus IE2 "accelerator" circuit, indicating that IE accelerator circuitry is shared among the alpha and beta herpesviruses. We speculate that this circuit motif is a common evolutionary countermeasure to throttle IE expression and thereby minimize the inherent cytotoxicity of these obligate viral transactivators.

Keywords: HSV-1; accelerator circuit; autoregulation; fitness advantage; herpesvirus; single-cell time-lapse imaging; transcriptional feedback.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chlorocebus aethiops
  • Herpesvirus 1, Human*
  • Immediate-Early Proteins* / genetics
  • Trans-Activators
  • Transcription Factors / genetics
  • Vero Cells


  • Immediate-Early Proteins
  • Trans-Activators
  • Transcription Factors