Long terminal repeat circular DNA as markers of active viral replication of human t lymphotropic Virus-1 in vivo

James M. Fox, Silva Hilburn, Maria Antonietta Demontis, David W. Brighty, Maria Fernanda Rios Grassi, Bernardo Galvão-Castro, Graham P. Taylor, Fabiola Martin (Lead / Corresponding author)

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    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.

    Original languageEnglish
    Article number80
    Pages (from-to)1-15
    Number of pages15
    JournalViruses
    Volume8
    Issue number3
    DOIs
    Publication statusPublished - 14 Mar 2016

    Fingerprint

    Circular DNA
    Human T-lymphotropic virus 1
    Terminal Repeat Sequences
    Genetic Markers
    Viruses
    DNA
    Tropical Spastic Paraparesis
    RNA-Directed DNA Polymerase
    HIV-1
    Blood Cells
    RNA
    Adult T Cell Leukemia Lymphoma
    Spinal Cord Diseases
    Virus Replication
    Infection
    Viral Load

    Keywords

    • HTLV
    • Human T-lymphotropic virus
    • Long terminal repeat
    • LTR DNA circles
    • Viral replication

    Cite this

    Fox, J. M., Hilburn, S., Demontis, M. A., Brighty, D. W., Grassi, M. F. R., Galvão-Castro, B., ... Martin, F. (2016). Long terminal repeat circular DNA as markers of active viral replication of human t lymphotropic Virus-1 in vivo. Viruses, 8(3), 1-15. [80]. https://doi.org/10.3390/v8030080
    Fox, James M. ; Hilburn, Silva ; Demontis, Maria Antonietta ; Brighty, David W. ; Grassi, Maria Fernanda Rios ; Galvão-Castro, Bernardo ; Taylor, Graham P. ; Martin, Fabiola. / Long terminal repeat circular DNA as markers of active viral replication of human t lymphotropic Virus-1 in vivo. In: Viruses. 2016 ; Vol. 8, No. 3. pp. 1-15.
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    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.",
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    note = "We wish to acknowledge the patients that provided the samples used in this study. Funding for the in vitro and ex vivo studies was from a University of York and Hull York Medical School pump priming fund awarded to FM; purchase of the HuT 102 cells and JMF was funded by a University of York biology departmental fellowship funded by a Wellcome Trust Value in People award, reference 092430/Z/10/Z. GPT is supported by Imperial NIHR Biomedical Research Centre (BRC). BGC and MFRG are funded by Funda{\cc}{\~a}o de Amparo a Pesquisa do Estado da Bahia (FAPESB) and Brazilian National Council of Technological and Scientific Development (CNPq). DWB is funded by the Leukaemia and Lymphoma Research (LLR) grants LLR 12041 and LLR 09006.",
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    Fox, JM, Hilburn, S, Demontis, MA, Brighty, DW, Grassi, MFR, Galvão-Castro, B, Taylor, GP & Martin, F 2016, 'Long terminal repeat circular DNA as markers of active viral replication of human t lymphotropic Virus-1 in vivo', Viruses, vol. 8, no. 3, 80, pp. 1-15. https://doi.org/10.3390/v8030080

    Long terminal repeat circular DNA as markers of active viral replication of human t lymphotropic Virus-1 in vivo. / Fox, James M.; Hilburn, Silva; Demontis, Maria Antonietta; Brighty, David W.; Grassi, Maria Fernanda Rios; Galvão-Castro, Bernardo; Taylor, Graham P.; Martin, Fabiola (Lead / Corresponding author).

    In: Viruses, Vol. 8, No. 3, 80, 14.03.2016, p. 1-15.

    Research output: Contribution to journalArticle

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    AU - Demontis, Maria Antonietta

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    AU - Grassi, Maria Fernanda Rios

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    AU - Taylor, Graham P.

    AU - Martin, Fabiola

    N1 - We wish to acknowledge the patients that provided the samples used in this study. Funding for the in vitro and ex vivo studies was from a University of York and Hull York Medical School pump priming fund awarded to FM; purchase of the HuT 102 cells and JMF was funded by a University of York biology departmental fellowship funded by a Wellcome Trust Value in People award, reference 092430/Z/10/Z. GPT is supported by Imperial NIHR Biomedical Research Centre (BRC). BGC and MFRG are funded by Fundação de Amparo a Pesquisa do Estado da Bahia (FAPESB) and Brazilian National Council of Technological and Scientific Development (CNPq). DWB is funded by the Leukaemia and Lymphoma Research (LLR) grants LLR 12041 and LLR 09006.

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    N2 - 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.

    AB - 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.

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    KW - Human T-lymphotropic virus

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    KW - Viral replication

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    Fox JM, Hilburn S, Demontis MA, Brighty DW, Grassi MFR, Galvão-Castro B et al. Long terminal repeat circular DNA as markers of active viral replication of human t lymphotropic Virus-1 in vivo. Viruses. 2016 Mar 14;8(3):1-15. 80. https://doi.org/10.3390/v8030080