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

TY - JOUR

T1 - Long terminal repeat circular DNA as markers of active viral replication of human t lymphotropic Virus-1 in vivo

AU - Fox, James M.

AU - Hilburn, Silva

AU - Demontis, Maria Antonietta

AU - Brighty, David W.

AU - Grassi, Maria Fernanda Rios

AU - Galvão-Castro, Bernardo

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.

PY - 2016/3/14

Y1 - 2016/3/14

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.

KW - HTLV

KW - Human T-lymphotropic virus

KW - Long terminal repeat

KW - LTR DNA circles

KW - Viral replication

UR - https://www.scopus.com/pages/publications/84961249457

U2 - 10.3390/v8030080

DO - 10.3390/v8030080

M3 - Article

C2 - 26985903

AN - SCOPUS:84961249457

VL - 8

SP - 1

EP - 15

JO - Viruses

JF - Viruses

IS - 3

M1 - 80

ER -