Fate-Regulating Circuits in Viruses: From Discovery to New Therapy Targets

Annu Rev Virol. 2017 Sep 29;4(1):469-490. doi: 10.1146/annurev-virology-110615-035606. Epub 2017 Aug 11.


Current antivirals effectively target diverse viruses at various stages of their life cycles. Nevertheless, curative therapy has remained elusive for important pathogens, such as human immunodeficiency virus type 1 (HIV-1) and herpesviruses, in large part due to viral latency and the evolution of resistance to existing therapies. Here, we review the discovery of viral master circuits: virus-encoded autoregulatory gene networks that autonomously control viral expression programs (i.e., between active, latent, and abortive fates). These circuits offer the opportunity for a new class of antivirals that could lead to intrinsic combination-antiviral therapies within a single molecule-evolutionary escape from such circuit-disrupting antivirals would require simultaneous evolution of both the viral cis regulatory element (e.g., the DNA-binding site) and the trans element (e.g., the transcription factor) in order for the virus to recapitulate a circuit that would not be disrupted. We review the architectures of these fate-regulating master circuits in HIV-1 and the human herpesvirus cytomegalovirus along with potential circuit-disruption strategies that may ultimately enable escape-resistant antiviral therapies.

Keywords: CMV; HIV; autoregulatory circuits; fate regulation; feedback; latency; stochastic noise; transcription; transcriptional fluctuations.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Antiviral Agents / pharmacology*
  • Cytomegalovirus / drug effects
  • Cytomegalovirus / genetics*
  • Cytomegalovirus / physiology
  • Feedback, Physiological
  • Gene Expression Regulation, Viral*
  • Gene Regulatory Networks*
  • HIV-1 / drug effects
  • HIV-1 / genetics*
  • HIV-1 / physiology
  • Humans
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Virus Latency
  • tat Gene Products, Human Immunodeficiency Virus / metabolism


  • Anti-HIV Agents
  • Antiviral Agents
  • Transcription Factors
  • tat Gene Products, Human Immunodeficiency Virus