Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex

PLoS Pathog. 2014 Apr 3;10(4):e1004040. doi: 10.1371/journal.ppat.1004040. eCollection 2014 Apr.


Human T lymphotropic virus type I (HTLV-I) infection is largely latent in infected persons. How HTLV-1 establishes latency and reactivates is unclear. Here we show that most HTLV-1-infected HeLa cells become senescent. By contrast, when NF-κB activity is blocked, senescence is averted, and infected cells continue to divide and chronically produce viral proteins. A small population of infected NF-κB-normal HeLa cells expresses low but detectable levels of Tax and Rex, albeit not Gag or Env. In these "latently" infected cells, HTLV-1 LTR trans-activation by Tax persists, but NF-κB trans-activation is attenuated due to inhibition by HBZ, the HTLV-1 antisense protein. Furthermore, Gag-Pol mRNA localizes primarily in the nuclei of these cells. Importantly, HBZ was found to inhibit Rex-mediated export of intron-containing mRNAs. Over-expression of Rex or shRNA-mediated silencing of HBZ led to viral reactivation. Importantly, strong NF-κB inhibition also reactivates HTLV-1. Hence, during HTLV-1 infection, when Tax/Rex expression is robust and dominant over HBZ, productive infection ensues with expression of structural proteins and NF-κB hyper-activation, which induces senescence. When Tax/Rex expression is muted and HBZ is dominant, latent infection is established with expression of regulatory (Tax/Rex/HBZ) but not structural proteins. HBZ maintains viral latency by down-regulating Tax-induced NF-κB activation and senescence, and by inhibiting Rex-mediated expression of viral structural proteins.

Publication types

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

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Cell Nucleus / virology
  • Gene Expression Regulation, Viral / physiology*
  • Gene Products, rex / genetics
  • Gene Products, rex / metabolism*
  • Gene Products, tax
  • HTLV-I Infections / genetics
  • HTLV-I Infections / metabolism*
  • HeLa Cells
  • Human T-lymphotropic virus 1 / physiology*
  • Humans
  • RNA, Viral / biosynthesis
  • RNA, Viral / genetics
  • Retroviridae Proteins
  • Transcriptional Activation / physiology*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*
  • Virus Latency / physiology*


  • Basic-Leucine Zipper Transcription Factors
  • Gene Products, rex
  • Gene Products, tax
  • HBZ protein, human T-cell leukemia virus type I
  • RNA, Viral
  • Retroviridae Proteins
  • Viral Proteins
  • rex Protein, Human T-lymphotropic virus 1
  • tax protein, Human T-lymphotrophic virus 1