The host genomic environment of the provirus determines the abundance of HTLV-1-infected T-cell clones.

N. Gillet, N. Malani, A. Melamed, N. Gormley, Michael R. Carter, D. Bentley, C. C. Berry, F. D. Bushman, G. P. Taylor, C. R. M. Bangham

Research output: Contribution to journalArticlepeer-review

Abstract

[en] Human T-lymphotropic virus type 1 (HTLV-1) persists by driving clonal proliferation of infected T lymphocytes. A high proviral load predisposes to HTLV-1-associated diseases. Yet the reasons for the variation within and between persons in the abundance of HTLV-1-infected clones remain unknown. We devised a high-throughput protocol to map the genomic location and quantify the abundance of > 91,000 unique insertion sites of the provirus from 61 HTLV-1(+) persons and > 2100 sites from in vitro infection. We show that a typical HTLV-1-infected host carries between 500 and 5000 unique insertion sites. We demonstrate that negative selection dominates during chronic infection, favoring establishment of proviruses integrated in transcriptionally silenced DNA: this selection is significantly stronger in asymptomatic carriers. We define a parameter, the oligoclonality index, to quantify clonality. The high proviral load characteristic of HTLV-1-associated inflammatory disease results from a larger number of unique insertion sites than in asymptomatic carriers and not, as previously thought, from a difference in clonality. The abundance of established HTLV-1 clones is determined by genomic features of the host DNA flanking the provirus. HTLV-1 clonal expansion in vivo is favored by orientation of the provirus in the same sense as the nearest host gene.
Original languageEnglish
JournalBlood
Volume117
Issue number11
DOIs
Publication statusPublished - 2011
Externally publishedYes

Keywords

  • Sciences de la santé humaine => Oncologie
  • Cell Proliferation
  • Clone Cells
  • Epigenesis, Genetic
  • Genome, Human/genetics
  • HTLV-I Infections/genetics/immunology/virology
  • Host-Pathogen Interactions/genetics
  • Human T-lymphotropic virus 1/physiology
  • Humans
  • Middle Aged
  • Mutagenesis, Insertional/genetics
  • Polymerase Chain Reaction
  • Proviruses/genetics
  • T-Lymphocytes/pathology/virology
  • Time Factors
  • Transcription, Genetic
  • Virus Integration/genetics

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