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 language | English |
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Journal | Blood |
Volume | 117 |
Issue number | 11 |
DOIs | |
Publication status | Published - 2011 |
Externally published | Yes |
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