title: Clonality of HTLV-2 in natural infection.
abstract: Human T-lymphotropic virus type 1 (HTLV-1) and type 2 (HTLV-2) both cause lifelong persistent infections, but differ in their clinical outcomes. HTLV-1 infection causes a chronic or acute T-lymphocytic malignancy in up to 5% of infected individuals whereas HTLV-2 has not been unequivocally linked to a T-cell malignancy. Virus-driven clonal proliferation of infected cells both in vitro and in vivo has been demonstrated in HTLV-1 infection. However, T-cell clonality in HTLV-2 infection has not been rigorously characterized. In this study we used a high-throughput approach in conjunction with flow cytometric sorting to identify and quantify HTLV-2-infected T-cell clones in 28 individuals with natural infection. We show that while genome-wide integration site preferences in vivo were similar to those found in HTLV-1 infection, expansion of HTLV-2-infected clones did not demonstrate the same significant association with the genomic environment of the integrated provirus. The proviral load in HTLV-2 is almost confined to CD8+ T-cells and is composed of a small number of often highly expanded clones. The HTLV-2 load correlated significantly with the degree of dispersion of the clone frequency distribution, which was highly stable over ∼8 years. These results suggest that there are significant differences in the selection forces that control the clonal expansion of virus-infected cells in HTLV-1 and HTLV-2 infection. In addition, our data demonstrate that strong virus-driven proliferation per se does not predispose to malignant transformation in oncoretroviral infections.
authors.affiliation: Section of Immunology, Imperial College London, Wright-Fleming Institute, London, United Kingdom.
authors.forename: Anat
authors.initials: A
authors.lastname: Melamed
authors.affiliation: Section of Immunology, Imperial College London, Wright-Fleming Institute, London, United Kingdom.
authors.forename: Aviva D
authors.initials: AD
authors.lastname: Witkover
authors.affiliation: Section of Immunology, Imperial College London, Wright-Fleming Institute, London, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Laydon
authors.affiliation: Section of Immunology, Imperial College London, Wright-Fleming Institute, London, United Kingdom.
authors.forename: Rachael
authors.initials: R
authors.lastname: Brown
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Kelly
authors.initials: K
authors.lastname: Miners
authors.affiliation: Section of Immunology, Imperial College London, Wright-Fleming Institute, London, United Kingdom.
authors.forename: Aileen G
authors.initials: AG
authors.lastname: Rowan
authors.affiliation: Illumina, Little Chesterford, Essex, United Kingdom.
authors.forename: Niall
authors.initials: N
authors.lastname: Gormley
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Section of Infectious Diseases, Imperial College London, Wright-Fleming Institute, London, United Kingdom.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Taylor
authors.affiliation: Departments of Laboratory Medicine and Epidemiology/Biostatistics, University of California San Francisco and Blood Systems Research Institute, San Francisco, California, United States of America.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Murphy
authors.affiliation: Section of Immunology, Imperial College London, Wright-Fleming Institute, London, United Kingdom.
authors.forename: Charles R M
authors.initials: CR
authors.lastname: Bangham
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000821:virology*; D002999:Clone Cells / Q000821:virology; D019295:Computational Biology; D005434:Flow Cytometry; D015490:HTLV-I Infections / Q000235:genetics / Q000821:virology; D015491:HTLV-II Infections / Q000235:genetics* / Q000821:virology*; D057166:High-Throughput Screening Assays; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D015367:Human T-lymphotropic virus 2 / Q000235:genetics; D006801:Humans; D011533:Proviruses / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019562:Viral Load / Q000235:genetics; D016662:Virus Integration / Q000235:genetics