Feedback-mediated signal conversion promotes viral fitness

Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):E8803-E8810. doi: 10.1073/pnas.1802905115. Epub 2018 Aug 27.


A fundamental signal-processing problem is how biological systems maintain phenotypic states (i.e., canalization) long after degradation of initial catalyst signals. For example, to efficiently replicate, herpesviruses (e.g., human cytomegalovirus, HCMV) rapidly counteract cell-mediated silencing using transactivators packaged in the tegument of the infecting virion particle. However, the activity of these tegument transactivators is inherently transient-they undergo immediate proteolysis but delayed synthesis-and how transient activation sustains lytic viral gene expression despite cell-mediated silencing is unclear. By constructing a two-color, conditional-feedback HCMV mutant, we find that positive feedback in HCMV's immediate-early 1 (IE1) protein is of sufficient strength to sustain HCMV lytic expression. Single-cell time-lapse imaging and mathematical modeling show that IE1 positive feedback converts transient transactivation signals from tegument pp71 proteins into sustained lytic expression, which is obligate for efficient viral replication, whereas attenuating feedback decreases fitness by promoting a reversible silenced state. Together, these results identify a regulatory mechanism enabling herpesviruses to sustain expression despite transient activation signals-akin to early electronic transistors-and expose a potential target for therapeutic intervention.

Keywords: feedback circuitry; mathematical model; single-cell imaging; virus.

Publication types

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

MeSH terms

  • Cell Line
  • Cells, Cultured
  • Cytomegalovirus / genetics*
  • Cytomegalovirus / physiology
  • Feedback, Physiological*
  • Gene Expression Regulation, Viral*
  • Host-Pathogen Interactions
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism
  • Microscopy, Fluorescence
  • Retinal Pigment Epithelium / cytology
  • Retinal Pigment Epithelium / virology
  • Time-Lapse Imaging / methods
  • Virus Replication / genetics*


  • IE1 protein, cytomegalovirus
  • Immediate-Early Proteins