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

Feedback-mediated signal conversion promotes viral fitness.

Author information

1
Gladstone-University of California, San Francisco (UCSF) Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158.
2
Gladstone-University of California, San Francisco (UCSF) Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158; leor.weinberger@gladstone.ucsf.edu.
3
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.
4
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158.

Abstract

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

PMID:
30150412
PMCID:
PMC6140503
DOI:
10.1073/pnas.1802905115
[Indexed for MEDLINE]
Free PMC Article

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