Whole body clonality analysis in an aggressive STLV-1 associated leukemia (ATLL) reveals an unexpected clonal complexity

Turpin, Jocelyn; Alais, Sandrine; Marçais, Ambroise; Bruneau, Julie; Melamed, Anat; Gadot, Nicolas; Tanaka, Yuetsu; Hermine, Olivier; Melot, Sandrine; Lacoste, Romain; Bangham, Charles R. M.; Mahieux, Renaud

doi:10.1016/j.canlet.2016.12.022

Cited by 14 publications

(19 citation statements)

References 47 publications

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“…Replication of HTLV-1 occurs either by infection of new cells, or by mitotic division and clonal proliferation of infected CD4 + T-cells ( Carpentier et al, 2015 ; Turpin et al, 2017 ). Cell-cell contacts are a prerequisite for efficient infection of CD4 + T-cells, while DC can be infected cell-free with viral biofilms ( Alais et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Quantitating the Transfer of the HTLV-1 p8 Protein Between T-Cells by Flow Cytometry

2018

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The Human T-cell leukemia virus type 1 (HTLV-1)-encoded accessory protein p8 is cleaved from the precursor protein p12 encoded by the HTLV-1 open reading frame I. Both p12 and p8 are thought to contribute to efficient viral persistence. Mechanistically, p8 induces T-cell conjugates and cellular conduits. The latter are considered to facilitate transfer of p8 to target cells and virus transmission. Transfer of p8 between p8-expressing T-cells and recipient cells has been analyzed by immunofluorescence and live imaging. However, automatic quantitation of p8-transfer between cells has not been studied yet. Here we developed a novel method allowing time saving quantitation of p8 transfer between cells by flow cytometry. After establishing a protocol for the detection of intracellular p8 by flow cytometry and validation of p8 protein expression by western blot and immunofluorescence, we set up a co-culture assay between p8-expressing donor Jurkat T-cells and recipient Jurkat T-cells that had been prestained with a well-retained live cell dye. Upon quantitating the amount of p8 positive recipient cells with regard to the percentage of p8 expressing donor cells, time course experiments confirmed that p8 is rapidly transferred between Jurkat T-cells. We found that p8 enters approximately 5% of recipient T-cells immediately upon co-culture for 5 min. Prolonged co-culture for up to 24 h revealed an increase of relative p8 transfer to approximately 23% of the recipient cells. Immunofluorescence analysis of co-culture experiments and manual quantitation of p8 expression in fluorescence images confirmed the validity of the flow cytometry based assay. Application of the new assay revealed that manipulation of actin polymerization significantly decreased p8 transfer between Jurkat T-cells suggesting an important role of actin dynamics contributing to p8 transfer. Further, transfer of p8 to co-cultured T-cells varies between different donor cell types since p8 transfer could hardly been detected in co-cultures of 293T donor cells with Jurkat acceptor cells. In summary, our novel assay allows automatic and rapid quantitation of p8 transfer to target cells and might thus contribute to a better understanding of cellular processes and dynamics regulating p8 transfer and HTLV-1 transmission.

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Section: Introductionmentioning

confidence: 99%

Quantitating the Transfer of the HTLV-1 p8 Protein Between T-Cells by Flow Cytometry

2018

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“…Second, the high number of viral particles transmitted through cell-cell contact could circumvent antiviral therapy efficiency, as observed for HIV-1 [ 62 ]. Finally, HTLV-1-infected cells can be found in organs that are poorly targeted by antivirals, such as lymph nodes [ 63 ], thymus [ 64 ], or bone marrow after the infection of bone–marrow hematopoietic stem cells [ 65 ], thus allowing persistent replication even under active retroviral treatment, as observed in HIV-1 infection [ 66 ].…”

Section: Viral Disseminationmentioning

confidence: 99%

“…Tax-mediated immortalization of HTLV-1 infected T-cells, and their subsequent mitotic divisions, will lead to the presence of expanded clones of HTLV-1 infected T-cells in infected individuals, which may persist for decades [ 75 ]. Even though the mechanisms regulating HTLV-1 clonality in vivo, i.e., determining the diversity of infected cells with different HTLV-1 integration sites, are not fully understood, oligoclonal expansion rather than monoclonal expansion of a given infected cell, could predispose to HTLV-1-associated diseases [ 63 ]. Furthermore, several factors other than clonality index are potentially involved in HTLV-1-associated diseases development, including proviral load itself, the number of infected cells transmitted from one individual to another one, or the immune response.…”

Section: Viral Disseminationmentioning

confidence: 99%

HTLV-1, the Other Pathogenic Yet Neglected Human Retrovirus: From Transmission to Therapeutic Treatment

Futsch

Mahieux

Dutartre

2017

Viruses

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Going back to their discovery in the early 1980s, both the Human T-cell Leukemia virus type-1 (HTLV-1) and the Human Immunodeficiency Virus type-1 (HIV-1) greatly fascinated the virology scene, not only because they were the first human retroviruses discovered, but also because they were associated with fatal diseases in the human population. In almost four decades of scientific research, both viruses have had different fates, HTLV-1 being often upstaged by HIV-1. However, although being very close in terms of genome organization, cellular tropism, and viral replication, HIV-1 and HTLV-1 are not completely commutable in terms of treatment, especially because of the opposite fate of the cells they infect: death versus immortalization, respectively. Nowadays, the antiretroviral therapies developed to treat HIV-1 infected individuals and to limit HIV-1 spread among the human population have a poor or no effect on HTLV-1 infected individuals, and thus, do not prevent the development of HTLV-1-associated diseases, which still lack highly efficient treatments. The present review mainly focuses on the course of HTLV-1 infection, from the initial infection of the host to diseases development and associated treatments, but also investigates HIV-1/HTLV-1 co-infection events and their impact on diseases development.

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“…A recent report showed that STLV-4 was isolated from gorillas and that the virus was endemic to gorillas [29]. It has been reported that STLVs originated from African nonhuman primates are pathogenic to the natural hosts and are associated with leukemia/lymphoma [30][31][32][33]. The zoonotic STLV transmission to humans is likely caused by hunting and severe bites of nonhuman primates [20,[34][35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

Frequent horizontal and mother-to-child transmission may contribute to high prevalence of STLV-1 infection in Japanese macaques

Murata

Yasunaga

Washizaki

et al. 2020

Preprint

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Background: Simian T-cell leukemia virus type-1 (STLV-1) is disseminated among various non-human primate species and is closely related to human T-cell leukemia virus type-1 (HTLV-1), the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/ tropical spastic paraparesis. Notably, t he prevalence of STLV-1 infection in Japanese macaques (JMs) is estimated to be >60%, much greater than that in other non-human primates; however, the mechanism and mode of STLV-1 transmission remain unknown. The aim of this study is to examine the epidemiological background by which STLV-1 infection is highly prevalent in JMs. Results: The prevalence of STLV-1 in the JMs rearing in our free-range facility reached up to 64% (180/280 JMs) with variation from 55 to 77% among five independent troops. Anti-STLV-1 antibody titers (ABTs) and STLV-1 proviral loads ( PVLs) were normally distributed with mean values of 4076 and 0.62%, respectively, which were mostly comparable to those of HTLV-1-infected humans. Our initial hypothesis that some of the macaques might contribute to frequent horizontal STLV-1 transmission as viral super-spreaders was unlikely because of the absence of the macaques exhibiting abnormally high PVLs but poor ABTs. Rather, ABTs and PVLs were statically corelated (p < 0.0001), indicating that the increasing PVLs led to the greater humoral immune response. Further analyses demonstrated that the STLV-1 prevalence as determined by detection of the proviral DNA was dramatically increased with age; 11%, 31%, and 58% at 0, 1, and 2 years of age, which was generally consistent with the result of seroprevalence and suggested the frequent incidence of mother-to-child transmission (MTCT). Moreover, our longitudinal follow-up study indicated that 24 of 28 seronegative JMs during the periods from 2011 to 2012 converted to seropositive (86%) four years later; among them, the seroconversion rates of sexually matured (4 years of age and older) macaques and immature macaques (3 years of age and younger) at the beginning of study were comparably high (80% and 89%, respectively), suggesting the frequent incidence of horizontal transmission. Conclusions: Together with the fact that almost all of the full-adult JMs older than 9 years old were infected with STLV-1, our results of this study demonstrated for the first time that frequent horizontal and mother-to-child transmission may contribute to high prevalence of STLV-1 infection in JMs

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Whole body clonality analysis in an aggressive STLV-1 associated leukemia (ATLL) reveals an unexpected clonal complexity

Cited by 14 publications

References 47 publications

Quantitating the Transfer of the HTLV-1 p8 Protein Between T-Cells by Flow Cytometry

Quantitating the Transfer of the HTLV-1 p8 Protein Between T-Cells by Flow Cytometry

HTLV-1, the Other Pathogenic Yet Neglected Human Retrovirus: From Transmission to Therapeutic Treatment

Frequent horizontal and mother-to-child transmission may contribute to high prevalence of STLV-1 infection in Japanese macaques

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