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

• Published in: Blood 2011-03, Vol.117 (11), p.3113-3122
• Main Authors: Gillet, Nicolas A., Malani, Nirav, Melamed, Anat, Gormley, Niall, Carter, Richard, Bentley, David, Berry, Charles, Bushman, Frederic D., Taylor, Graham P., Bangham, Charles R.M.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell Proliferation; Clone Cells; Epigenesis, Genetic; Genome, Human - genetics; Hematologic and hematopoietic diseases; Host-Pathogen Interactions - genetics; HTLV-I Infections - genetics; HTLV-I Infections - immunology; HTLV-I Infections - virology; HTLV-I Infections/genetics/immunology/virology; Human health sciences; Human T-lymphotropic virus 1 - physiology; Humans; Immunobiology; Medical sciences; Middle Aged; Mutagenesis, Insertional - genetics; Oncologie; Oncology; Polymerase Chain Reaction; Proviruses - genetics; Sciences de la santé humaine; T-Lymphocytes - pathology; T-Lymphocytes - virology; T-Lymphocytes/pathology/virology; Time Factors; Transcription, Genetic; Virus Integration - genetics
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-10-312926

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.