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

Furuta, Rie; Yasunaga, Jun-ichirou; Miura, Michi; Sugata, Kenji; Saito, Akatsuki; Akari, Hirofumi; Ueno, Takaharu; Takenouchi, Norihiro; Fujisawa, Jun; Koh, Ki Ryang; Higuchi, Yusuke; Mahgoub, Mohamed; Shimizu, Masakazu; Matsuda, Fumihiko; Melamed, Anat; Bangham, Charles R. M.; Matsuoka, Masao

doi:10.1371/journal.ppat.1006722

Cited by 61 publications

(66 citation statements)

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“…Generation of HTLV-1-infected cells in vitro 293T cells transfected with pX1 plasmid, an HTLV-1 molecular clone (Mitchell et al, 2007), by Polyethylenimine (PEI), and then were irradiated with 30 Gy. The irradiated 293T cells were co-cultured with JET cells for 3 days (Furuta et al, 2017). Then, tdTomato positive cells, which is induced by Tax in the cells, were sorted by FACSAria, and cultured in RPMI supplemented with 10% FBS, 100 U/ml penicillin and 100 mg/ml streptomycin for 2, 8, or 16 weeks.…”

Section: Methods Detailsmentioning

confidence: 99%

The Nature of the HTLV-1 Provirus in Naturally Infected Individuals Analyzed by the Viral DNA-Capture-Seq Approach

Katsuya¹,

Islam²,

Tan³

et al. 2019

Cell Reports

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Graphical Abstract Highlights d A method for comprehensive analysis of HTLV-1 proviruses in infected individuals d The method provides viral sequence, integration site, and degree of cell expansion d Defective proviruses are present in asymptomatic carriers and HAM/TSP, as well as ATL d Infected cells with defective proviruses proliferate more than those with intact ones Correspondence y-satou@kumamoto-u.ac.jp In Brief Katsuya et al. demonstrate that HTLV-1 DNA-capture-seq provides comprehensive information, including the entire viral sequence, integration site, and clonal abundance of infected cells.Infected clones with defective-type proviruses are present in disease states and in asymptomatic carriers, and they proliferate more than full-length proviruses. SUMMARYThe retrovirus human T-cell leukemia virus type 1 (HTLV-1) integrates into the host DNA, achieves persistent infection, and induces human diseases.Here, we demonstrate that viral DNA-capture sequencing (DNA-capture-seq) is useful to characterize HTLV-1 proviruses in naturally virus-infected individuals, providing comprehensive information about the proviral structure and the viral integration site. We analyzed peripheral blood from 98 naturally HTLV-1-infected individuals and found that defective proviruses were present not only in patients with leukemia, but also in those with other clinical entities. We further demonstrated that clones with defective-type proviruses exhibited a higher degree of clonal abundance than those with full-length proviruses. The frequency of defective-type proviruses in HTLV-1-infected humanized mice was lower than that in infected individuals, indicating that defective proviruses were rare at the initial phase of infection but preferentially selected during persistent infection. These results demonstrate the robustness of viral DNA-captureseq for HTLV-1 infection and suggest potential applications for other virus-associated cancers in humans.

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Section: Methods Detailsmentioning

confidence: 99%

The Nature of the HTLV-1 Provirus in Naturally Infected Individuals Analyzed by the Viral DNA-Capture-Seq Approach

Katsuya¹,

Islam²,

Tan³

et al. 2019

Cell Reports

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“…We postulate that HTLV-1 expresses tax in different anatomical compartments of the body other than the blood, such as bone marrow and lymphatic organs. This notion is supported by the observation that tax is highly expressed in bone marrow in Japanese macaques infected with simian leukemia virus STLV-1, the simian counterpart of HTLV-1 [22]. The smFISH technique could be applied to analyse specimens from those organs, to identify and localise the subset of cells that express tax, and to reveal the structural and spatial distribution of HTLV-1 expression in situ.…”

Section: Discussionmentioning

confidence: 93%

Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling

Miura

Dey

Singh

et al. 2019

Preprint

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20The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-21 strand transcription is usually silent at a given time in each cell. However, cellular stress responses 22 trigger the reactivation of HTLV-1, enabling the virus to transmit to a new host cell. Using single-23 molecule RNA FISH, we measured the kinetics of the HTLV-1 transcriptional reactivation in peripheral 24 blood mononuclear cells (PBMCs) isolated from HTLV-1 + individuals. The abundance of the HTLV-1 sense 25 and antisense transcripts was quantified hourly during incubation of the HTLV-1-infected PBMCs ex vivo. 26We found that, in each cell, the sense-strand transcription occurs in two distinct phases: the initial low-27 rate transcription is followed by a phase of rapid transcription. The onset of transcription peaked 28 between 1 and 3 hours after the start of in vitro incubation. The variance in the transcription intensity 29 was similar in polyclonal HTLV-1 + PBMCs (with tens of thousands of distinct provirus insertion sites), and 30 in samples with a single dominant HTLV-1 + clone. A stochastic simulation model was developed to 31 estimate the parameters of HTLV-1 proviral transcription kinetics. In PBMCs from a leukemic subject 32 with one dominant T-cell clone, the model indicated that the average duration of HTLV-1 sense-strand 33 activation by Tax (i.e. the rapid transcription) was less than one hour. HTLV-1 antisense transcription 34 was stable during reactivation of the sense-strand. The antisense transcript HBZ was produced at an 35 average rate of ~0.1 molecules per hour per HTLV-1 + cell; however, between 20% and 70% of HTLV-1-36 infected cells were HBZ-negative at a given time, the percentage depending on the individual subject. 37 HTLV-1-infected cells are exposed to a range of stresses when they are drawn from the host, which 38 initiate the viral reactivation. We conclude that whereas antisense-strand transcription is stable 39 throughout the stress response, the HTLV-1 sense-strand reactivation is highly heterogeneous and 40 occurs in short, self-terminating bursts. 41 3 Author summary 42 Human retroviruses such as HIV-1 and HTLV-1 (human T cell leukemia virus) can establish a latent 43 infection in the host cell. However, these viruses need to be able to produce viral genome to propagate 44 in a new host. HTLV-1-infected cells are transmitted through breastfeeding, blood transfusion and sexual 45 contact, and HTLV-1 restores transcription once the infected cells are drawn from infected individuals. 46We measured the kinetics of the HTLV-1 transcriptional reactivation in blood cells isolated from HTLV-1 + 47 individuals by single-molecule RNA FISH. Viral transcripts were visualised as diffraction-limited spots and 48 their abundance was quantified at one-hour intervals. The onset of the virus transcription peaked after 49 one to three hours of incubation. In each cell, a short period of slow HTLV-1 transcription was followed 50 by a phase of rapid transcription. Computer simu...

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“…HTLV-1 is a complex retrovirus that mainly infects CD4+ T cells, although it has the potential to infect a wide variety of other cells: CD8+ T cells, B lymphocytes, myeloid cells, endothelial cells, fibroblasts, neutrophils, monocytes, myeloid and plasmacytoid dendritic cells [7][8][9][10]. Cell-free HTLV-1 virions have poor infectivity, and the spreading of this virus depends mainly on two cell-to-cell between HTLV-1 virological parameters or clinical status and the expression of TRIM5α and TRIM22.…”

Section: Htlv-1 Infection Cycle and Host Restriction Factors (Figure 1)mentioning

confidence: 99%

An Antiviral Process Targeting HTLV-1: The Complex Relationship between HTLV-1 and Nonsense-mediated mRNA Decay

Prochasson¹,

Jalinot²,

Mocquet³

2020

Preprint

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Before the adaptive immune response is established, retroviruses can be targeted by several cellular host factors at different stages of the viral replication cycle. This intrinsic immunity relies on a large diversity of antiviral processes. In the case of HTLV-1 infection, these active innate host defence mechanisms are debated. Among these mechanisms, we focused on a RNA decay pathway called nonsense-mediated mRNA decay (NMD), which can target multiple viral RNAs, including HTLV-1 unspliced RNA, as it has been recently demonstrated. NMD is a cotranslational process that depends on the RNA helicase UPF1 and regulates the expression of multiple types of host mRNAs. RNA sensitivity to NMD depends on mRNA organization and the ribonucleoprotein (mRNP) composition.HTLV-1 has evolved several means to evade the NMD threat, leading to NMD inhibition. In the early steps of infection, NMD inhibition favours the production of HTLV-1 infectious particles, which may contribute to the survival of the most fit clones despite genome instability; however, its direct longterm impact remains to be investigated.

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

Cited by 61 publications

References 50 publications

The Nature of the HTLV-1 Provirus in Naturally Infected Individuals Analyzed by the Viral DNA-Capture-Seq Approach

The Nature of the HTLV-1 Provirus in Naturally Infected Individuals Analyzed by the Viral DNA-Capture-Seq Approach

Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling

An Antiviral Process Targeting HTLV-1: The Complex Relationship between HTLV-1 and Nonsense-mediated mRNA Decay

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