Human Herpesvirus 6A Tegument Protein U14 Induces NF-κB Signaling by Interacting with p65

J Virol. 2021 Nov 9;95(23):e0126921. doi: 10.1128/JVI.01269-21. Epub 2021 Sep 22.


Viral infection induces host cells to mount a variety of immune responses, which may either limit viral propagation or create conditions conducive to virus replication in some instances. In this regard, activation of the NF-κB transcription factor is known to modulate virus replication. Human herpesvirus 6A (HHV-6A), which belongs to the Betaherpesvirinae subfamily, is frequently found in patients with neuroinflammatory diseases, although its role in disease pathogenesis has not been elucidated. In this study, we found that the HHV-6A-encoded U14 protein activates NF-κB signaling following interaction with the NF-κB complex protein, p65. Through induction of nuclear translocation of p65, U14 increases the expression of interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein 1 transcripts. We also demonstrated that activation of NF-κB signaling is important for HHV-6A replication, since inhibition of this pathway reduced virus protein accumulation and viral genome copy number. Taken together, our results suggest that HHV-6A infection activates the NF-κB pathway and promotes viral gene expression via late gene products, including U14. IMPORTANCE Human herpesvirus 6A (HHV-6A) is frequently found in patients with neuro-inflammation, although its role in the pathogenesis of this disease has not been elucidated. Most viral infections activate the NF-κB pathway, which causes the transactivation of various genes, including those encoding proinflammatory cytokines. Our results indicate that HHV-6A U14 activates the NF-κB pathway, leading to upregulation of proinflammatory cytokines. We also found that activation of the NF-κB transcription factor is important for efficient viral replication. This study provides new insight into HHV-6A U14 function in host cell signaling and identifies potential cellular targets involved in HHV-6A pathogenesis and replication.

Keywords: HHV-6; NF-κB; gene expression; herpes; tegument.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Gene Expression Regulation
  • Genes, Viral
  • Genome, Viral
  • Herpesvirus 6, Human / genetics*
  • Herpesvirus 6, Human / metabolism*
  • Humans
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neuroinflammatory Diseases
  • Receptor, EphB2
  • Roseolovirus Infections / immunology*
  • Signal Transduction / immunology*
  • Viral Proteins / genetics
  • Viral Proteins / immunology*
  • Virus Replication


  • NF-kappa B
  • Viral Proteins
  • EPHB2 protein, human
  • Receptor, EphB2