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

Blood. 2011 Mar 17;117(11):3113-22. doi: 10.1182/blood-2010-10-312926. Epub 2011 Jan 12.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation
  • Clone Cells
  • Epigenesis, Genetic
  • Genome, Human / genetics*
  • HTLV-I Infections / genetics*
  • HTLV-I Infections / immunology
  • HTLV-I Infections / 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
  • T-Lymphocytes / virology*
  • Time Factors
  • Transcription, Genetic
  • Virus Integration / genetics