title: The host genomic environment of the provirus determines the abundance of HTLV-1-infected T-cell clones.
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.
authors.affiliation: Department of Immunology, Wright-Fleming Institute, Imperial College London, London, UK. n.gillet@ulg.ac.be
authors.forename: Nicolas A
authors.initials: NA
authors.lastname: Gillet
authors.forename: Nirav
authors.initials: N
authors.lastname: Malani
authors.forename: Anat
authors.initials: A
authors.lastname: Melamed
authors.forename: Niall
authors.initials: N
authors.lastname: Gormley
authors.forename: Richard
authors.initials: R
authors.lastname: Carter
authors.forename: David
authors.initials: D
authors.lastname: Bentley
authors.forename: Charles
authors.initials: C
authors.lastname: Berry
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Graham P
authors.initials: GP
authors.lastname: Taylor
authors.forename: Charles R M
authors.initials: CR
authors.lastname: Bangham
mesh_terms: D049109:Cell Proliferation; D002999:Clone Cells; D044127:Epigenesis, Genetic; D015894:Genome, Human / Q000235:genetics*; D015490:HTLV-I Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D054884:Host-Pathogen Interactions / Q000235:genetics*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D016254:Mutagenesis, Insertional / Q000235:genetics; D016133:Polymerase Chain Reaction; D011533:Proviruses / Q000235:genetics*; D013601:T-Lymphocytes / Q000473:pathology / Q000821:virology*; D013997:Time Factors; D014158:Transcription, Genetic; D016662:Virus Integration / Q000235:genetics