Role for the shelterin protein TRF2 in human herpesvirus 6A/B chromosomal integration

PLoS Pathog. 2020 Apr 22;16(4):e1008496. doi: 10.1371/journal.ppat.1008496. eCollection 2020 Apr.


Human herpesviruses 6A and 6B (HHV-6A/B) are unique among human herpesviruses in their ability to integrate their genome into host chromosomes. Viral integration occurs at the ends of chromosomes within the host telomeres. The ends of the HHV-6A/B genomes contain telomeric repeats that facilitate the integration process. Here, we report that productive infections are associated with a massive increase in telomeric sequences of viral origin. The majority of the viral telomeric signals can be detected within viral replication compartments (VRC) that contain the viral DNA processivity factor p41 and the viral immediate-early 2 (IE2) protein. Components of the shelterin protein complex present at telomeres, including TRF1 and TRF2 are also recruited to VRC during infection. Biochemical, immunofluorescence coupled with in situ hybridization and chromatin immunoprecipitation demonstrated the binding of TRF2 to the HHV-6A/B telomeric repeats. In addition, approximately 60% of the viral IE2 protein localize at cellular telomeres during infection. Transient knockdown of TRF2 resulted in greatly reduced (13%) localization of IE2 at cellular telomeres (p<0.0001). Lastly, TRF2 knockdown reduced HHV-6A/B integration frequency (p<0.05), while no effect was observed on the infection efficiency. Overall, our study identified that HHV-6A/B IE2 localizes to telomeres during infection and highlight the role of TRF2 in HHV-6A/B infection and chromosomal integration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • DNA, Viral / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Herpesvirus 6, Human / genetics*
  • Herpesvirus 6, Human / metabolism*
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism
  • Roseolovirus Infections / genetics
  • Roseolovirus Infections / metabolism
  • Roseolovirus Infections / virology
  • Telomere / genetics
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism
  • Telomeric Repeat Binding Protein 2 / genetics*
  • Telomeric Repeat Binding Protein 2 / metabolism
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Virus Integration / genetics*
  • Virus Replication / genetics


  • DNA, Viral
  • DNA-Binding Proteins
  • Immediate-Early Proteins
  • TERF2 protein, human
  • Telomere-Binding Proteins
  • Telomeric Repeat Binding Protein 2
  • U95 protein, human herpesvirus 6B
  • Viral Proteins
  • shelterin, human
  • p41 protein, Human herpesvirus 6