title: Long Terminal Repeat Circular DNA as Markers of Active Viral Replication of Human T Lymphotropic Virus-1 in Vivo.
abstract: Clonal expansion of human T-lymphotropic virus type-1 (HTLV-1) infected cells in vivo is well documented. Unlike human immunodeficiency virus type 1 (HIV-1), HTLV-1 plasma RNA is sparse. The contribution of the "mitotic" spread of HTLV-1 compared with infectious spread of the virus to HTLV-1 viral burden in established infection is uncertain. Since extrachromosomal long terminal repeat (LTR) DNA circles are indicators of viral replication in HIV-1 carriers with undetectable plasma HIV RNA, we hypothesised that HTLV-1 LTR circles could indicate reverse transcriptase (RT) usage and infectious activity. 1LTR and 2LTR DNA circles were measured in HTLV-1 cell lines and peripheral blood mononuclear cells (PBMC) of asymptomatic carriers (ACs) and patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or adult T cell leukaemia/lymphoma (ATLL). 1LTR DNA circles were detected in 14/20 patients at a mean of 1.38/100 PBMC but did not differentiate disease status nor correlate with HTLV-1 DNA copies. 2LTR DNA circles were detected in 30/31 patients and at higher concentrations in patients with HTLV-1-associated diseases, independent of HTLV-1 DNA load. In an incident case the 2LTR DNA circle concentration increased 2.1 fold at the onset of HAM/TSP compared to baseline. Detectable and fluctuating levels of HTLV-1 DNA circles in patients indicate viral RT usage and virus replication. Our results indicate HTLV-1 viral replication capacity is maintained in chronic infection and may be associated with disease onset.
authors.affiliation: Centre for Immunology and Infection, Department of Biology &amp; Hull York Medical School, University of York, York YO10 5DD, UK. james.fox@york.ac.uk.
authors.forename: James M
authors.initials: JM
authors.lastname: Fox
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Imperial College, London W2 1PG, UK. s.hilburn@imperial.ac.uk.
authors.forename: Silva
authors.initials: S
authors.lastname: Hilburn
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Imperial College, London W2 1PG, UK. m.demontis@imperial.ac.uk.|The National Centre for Human Retrovirology/HTLV Clinic, Imperial College Healthcare NHS Trust, St Mary's Hospital, London W2 1NY, UK. m.demontis@imperial.ac.uk.
authors.forename: Maria-Antonietta
authors.initials: MA
authors.lastname: Demontis
authors.affiliation: Division of Cancer Research, Ninewells Hospital &amp; Medical School, University of Dundee, Dundee DD1 9SY, UK. d.w.brighty@dundee.ac.uk.
authors.forename: David W
authors.initials: DW
authors.lastname: Brighty
authors.affiliation: Oswaldo Cruz Foundation, Gonçalo Moniz Research Center-BA, Advanced Laboratory of Public Health, Salvador, Bahia, Candeal 40296-710, Brazil. grassi@bahia.fiocruz.br.
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Rios Grassi
authors.affiliation: HTLV-Centre Bahian School of Medicine, Salvador, Bahia 40050-420, Brazil. galvao@bahiana.edu.br.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Galvão-Castro
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Imperial College, London W2 1PG, UK. g.p.taylor@imperial.ac.uk.|The National Centre for Human Retrovirology/HTLV Clinic, Imperial College Healthcare NHS Trust, St Mary's Hospital, London W2 1NY, UK. g.p.taylor@imperial.ac.uk.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Taylor
authors.affiliation: Centre for Immunology and Infection, Department of Biology &amp; Hull York Medical School, University of York, York YO10 5DD, UK. fabiola.martin@hyms.ac.uk.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Martin
mesh_terms: D015415:Biomarkers / Q000032:analysis*; D001769:Blood / Q000821:virology; D002353:Carrier State / Q000821:virology; D002478:Cells, Cultured; D004270:DNA, Circular / Q000032:analysis* / Q000235:genetics; D005260:Female; D015490:HTLV-I Infections / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008297:Male; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D020079:Terminal Repeat Sequences; D014779:Virus Replication
chemical_list: D015415:Biomarkers; D004270:DNA, Circular; D012194:RNA-Directed DNA Polymerase
keywords: HTLV; LTR DNA circles; human T-lymphotropic virus; long terminal repeat; viral replication