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.
Highlights
Human T-lymphotropic virus type-1 (HTLV-1) is a complex retrovirus, in the genus Deltaretrovirus of the subfamily Orthoretrovirinae of the Retroviridae family of viruses
Our results indicate HTLV-1 viral replication capacity is maintained in chronic infection and may be associated with disease onset
We previously presented preliminary data on circularised long terminal repeat (LTR) DNA concentration in MT2 cells [48] but with revised methodology and using matched cell extracts we have found both 1 and 2LTR DNA circles in two cell lines: MT-2 and HuT 102 (Table 2) originally derived from HTLV-1 infected individuals [2,49,50]. 1LTR DNA circles were approximately half as frequent as 2LTR DNA
Summary
Human T-lymphotropic virus type-1 (HTLV-1) is a complex retrovirus, in the genus Deltaretrovirus of the subfamily Orthoretrovirinae of the Retroviridae family of viruses. It is an oncovirus causing adult T cell leukaemia/lymphoma (ATLL) [1,2] and is associated with a variety of Viruses 2016, 8, 80; doi:10.3390/v8030080 www.mdpi.com/journal/viruses. Retroviruses carry a diploid plus-strand RNA genome [5] as well as viral enzymes reverse transcriptase (RT), integrase, protease and RNase H. In the nucleus the linear un-integrated DNA is either inserted into the host genome or circularised (Figure S1) [6,7,8]. The circular DNA has been found in different configurations such as 1LTR [7,9,10], tandem 2LTR [11,12]
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