title: HTLV-1 proviral integration sites differ between asymptomatic carriers and patients with HAM/TSP.
abstract: BACKGROUND
  HTLV-1 causes proliferation of clonal populations of infected T cells in vivo, each clone defined by a unique proviral integration site in the host genome. The proviral load is strongly correlated with odds of the inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is evidence that asymptomatic HTLV-1 carriers (ACs) have a more effective CD8 + T cell response, including a higher frequency of HLA class I alleles able to present peptides from a regulatory protein of HTLV-1, HBZ. We have previously shown that specific features of the host genome flanking the proviral integration site favour clone survival and spontaneous expression of the viral transactivator protein Tax in naturally infected PBMCs ex vivo. However, the previous studies were not designed or powered to detect differences in integration site characteristics between ACs and HAM/TSP patients. Here, we tested the hypothesis that the genomic environment of the provirus differs systematically between ACs and HAM/TSP patients, and between individuals with strong or weak HBZ presentation.
  
  
  METHODS
  We used our recently described high-throughput protocol to map and quantify integration sites in 95 HAM/TSP patients and 68 ACs from Kagoshima, Japan, and 75 ACs from Kumamoto, Japan. Individuals with 2 or more HLA class I alleles predicted to bind HBZ peptides were classified 'strong' HBZ binders; the remainder were classified 'weak binders'.
  
  
  RESULTS
  The abundance of HTLV-1-infected T cell clones in vivo was correlated with proviral integration in genes and in areas with epigenetic marks associated with active regulatory elements. In clones of equivalent abundance, integration sites in genes and active regions were significantly more frequent in ACs than patients with HAM/TSP, irrespective of HBZ binding and proviral load. Integration sites in genes were also more frequent in strong HBZ binders than weak HBZ binders.
  
  
  CONCLUSIONS
  Clonal abundance is correlated with integration in a transcriptionally active genomic region, and these regions may promote cell proliferation. A clone that reaches a given abundance in vivo is more likely to be integrated in a transcriptionally active region in individuals with a more effective anti-HTLV-1 immune response, such those who can present HBZ peptides or those who remain asymptomatic.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Niederer
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Laydon
authors.forename: Anat
authors.initials: A
authors.lastname: Melamed
authors.forename: Marjet
authors.initials: M
authors.lastname: Elemans
authors.forename: Becca
authors.initials: B
authors.lastname: Asquith
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
authors.affiliation: Department of Immunology, Wright-Fleming Institute, Imperial College London, London W2 1PG, UK. c.bangham@imperial.ac.uk.
authors.forename: Charles R M
authors.initials: CR
authors.lastname: Bangham
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002353:Carrier State; D000939:Epitopes; D005786:Gene Expression Regulation / Q000502:physiology*; D005805:Genes, MHC Class I / Q000235:genetics / Q000502:physiology; D020022:Genetic Predisposition to Disease; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015493:Paraparesis, Tropical Spastic / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D011485:Protein Binding; D012191:Retroviridae Proteins; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D000939:Epitopes; C479751:HBZ protein, human T-cell leukemia virus type I; D012191:Retroviridae Proteins; D014764:Viral Proteins