Cell Size-Based Decision-Making of a Viral Gene Circuit

Cell Rep. 2018 Dec 26;25(13):3844-3857.e5. doi: 10.1016/j.celrep.2018.12.009.

Abstract

Latently infected T cells able to reinitiate viral propagation throughout the body remain a major barrier to curing HIV. Distinguishing between latently infected cells and uninfected cells will advance efforts for viral eradication. HIV decision-making between latency and active replication is stochastic, and drug cocktails that increase bursts of viral gene expression enhance reactivation from latency. Here, we show that a larger host-cell size provides a natural cellular mechanism for enhancing burst size of viral expression and is necessary to destabilize the latent state and bias viral decision-making. Latently infected Jurkat and primary CD4+ T cells reactivate exclusively in larger activated cells, while smaller cells remain silent. In addition, reactivation is cell-cycle dependent and can be modulated with cell-cycle-arresting compounds. Cell size and cell-cycle dependent decision-making of viral circuits may guide stochastic design strategies and applications in synthetic biology and may provide important determinants to advance diagnostics and therapies.

Publication types

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

MeSH terms

  • CD4-Positive T-Lymphocytes / pathology*
  • CD4-Positive T-Lymphocytes / virology*
  • Cell Cycle
  • Cell Size*
  • Cells, Cultured
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Genes, Viral*
  • HIV-1 / genetics
  • Humans
  • Models, Biological
  • Promoter Regions, Genetic / genetics
  • Terminal Repeat Sequences / genetics
  • Virus Activation / genetics
  • Virus Latency / genetics