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PLoS Pathog. 2017 Nov 29;13(11):e1006722. doi: 10.1371/journal.ppat.1006722. eCollection 2017 Nov.

Human T-cell leukemia virus type 1 infects multiple lineage hematopoietic cells in vivo.

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Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
Department of Hematology, Rheumatology, and Infectious Diseases, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Center for Human Evolution Modeling Research, Primate Research Institute, Kyoto University, Inuyama, Aich, Japan.
Laboratory of Infectious Disease Model, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
Department of Microbiology, Kansai Medical University, Hirakata, Osaka, Japan.
Department of Hematology, Osaka General Hospital of West Japan Railway Company, Osaka, Japan.
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Section of Virology, Department of Medicine, Imperial College London, London, United Kingdom.


Human T-cell leukemia virus type 1 (HTLV-1) infects mainly CD4+CCR4+ effector/memory T cells in vivo. However, it remains unknown whether HTLV-1 preferentially infects these T cells or this virus converts infected precursor cells to specialized T cells. Expression of viral genes in vivo is critical to study viral replication and proliferation of infected cells. Therefore, we first analyzed viral gene expression in non-human primates naturally infected with simian T-cell leukemia virus type 1 (STLV-1), whose virological attributes closely resemble those of HTLV-1. Although the tax transcript was detected only in certain tissues, Tax expression was much higher in the bone marrow, indicating the possibility of de novo infection. Furthermore, Tax expression of non-T cells was suspected in bone marrow. These data suggest that HTLV-1 infects hematopoietic cells in the bone marrow. To explore the possibility that HTLV-1 infects hematopoietic stem cells (HSCs), we analyzed integration sites of HTLV-1 provirus in various lineages of hematopoietic cells in patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and a HTLV-1 carrier using the high-throughput sequencing method. Identical integration sites were detected in neutrophils, monocytes, B cells, CD8+ T cells and CD4+ T cells, indicating that HTLV-1 infects HSCs in vivo. We also detected Tax protein in myeloperoxidase positive neutrophils. Furthermore, dendritic cells differentiated from HTLV-1 infected monocytes caused de novo infection to T cells, indicating that infected monocytes are implicated in viral spreading in vivo. Certain integration sites were re-detected in neutrophils from HAM/TSP patients at different time points, indicating that infected HSCs persist and differentiate in vivo. This study demonstrates that HTLV-1 infects HSCs, and infected stem cells differentiate into diverse cell lineages. These data indicate that infection of HSCs can contribute to the persistence and spread of HTLV-1 in vivo.

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