Abstract
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.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of adult T-cell leukemialymphoma (ATL) and inflammatory diseases including HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP) [1,2,3,4]
We show that HTLV-1 infects hematopoietic stem cells (HSCs), which differentiate into multiple lineages of hematopoietic cells, and likely act as viral reservoir, giving rise to infected neutrophils, monocytes and B cells
Infected T cells in the periphery are chimeric in origin: T cells newly infected in the periphery, and infected T cells differentiated from infected HSCs
Summary
Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of adult T-cell leukemialymphoma (ATL) and inflammatory diseases including HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP) [1,2,3,4]. HTLV-1 is a unique retrovirus since this virus transmits only by cell-to-cell infection [5,6,7]. The infectivity of free HTLV-1 virions is very inefficient whereas this virus transmits efficiently through cell-to-cell contact [8, 9]. HTLV-1 induces proliferation of infected cells to increase the chance of transmission [10,11,12]. There are two different ways to increase the number of HTLV-1-infected cells in vivo: proliferation of infected cells (mitotic division) and de novo infection [7]. It is thought that mitotic division is predominant in the chronic infection of this virus
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