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      Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells

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          Significance

          The oncogenic retrovirus human T-cell leukemia virus type 1 (HTLV-1) encodes Tax, an activator of both viral replication and cellular oncogenic pathways. Despite the potent activities of Tax, its precise roles in pathogenesis remain unclear, since it is faintly expressed in vivo. This study shows that sporadic and transient Tax expression is observed in a small subpopulation of HTLV-1–induced leukemic cells. This limited Tax expression is critical for survival of the whole population through ignition of antiapoptotic signals. Tax is induced by various stresses, suggesting that Tax efficiently protects cells from apoptosis and reactivates virus from reservoirs under conditions of cellular stress. It is an elaborated strategy of HTLV-1 to evade host immunity and enable persistence in vivo.

          Abstract

          Viruses causing chronic infection artfully manipulate infected cells to enable viral persistence in vivo under the pressure of immunity. Human T-cell leukemia virus type 1 (HTLV-1) establishes persistent infection mainly in CD4+ T cells in vivo and induces leukemia in this subset. HTLV-1–encoded Tax is a critical transactivator of viral replication and a potent oncoprotein, but its significance in pathogenesis remains obscure due to its very low level of expression in vivo. Here, we show that Tax is expressed in a minor fraction of leukemic cells at any given time, and importantly, its expression spontaneously switches between on and off states. Live cell imaging revealed that the average duration of one episode of Tax expression is ∼19 hours. Knockdown of Tax rapidly induced apoptosis in most cells, indicating that Tax is critical for maintaining the population, even if its short-term expression is limited to a small subpopulation. Single-cell analysis and computational simulation suggest that transient Tax expression triggers antiapoptotic machinery, and this effect continues even after Tax expression is diminished; this activation of the antiapoptotic machinery is the critical event for maintaining the population. In addition, Tax is induced by various cytotoxic stresses and also promotes HTLV-1 replication. Thus, it seems that Tax protects infected cells from apoptosis and increases the chance of viral transmission at a critical moment. Keeping the expression of Tax minimal but inducible on demand is, therefore, a fundamental strategy of HTLV-1 to promote persistent infection and leukemogenesis.

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          Most cited references 45

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          Creation of human tumour cells with defined genetic elements.

          During malignant transformation, cancer cells acquire genetic mutations that override the normal mechanisms controlling cellular proliferation. Primary rodent cells are efficiently converted into tumorigenic cells by the coexpression of cooperating oncogenes. However, similar experiments with human cells have consistently failed to yield tumorigenic transformants, indicating a fundamental difference in the biology of human and rodent cells. The few reported successes in the creation of human tumour cells have depended on the use of chemical or physical agents to achieve immortalization, the selection of rare, spontaneously arising immortalized cells, or the use of an entire viral genome. We show here that the ectopic expression of the telomerase catalytic subunit (hTERT) in combination with two oncogenes (the simian virus 40 large-T oncoprotein and an oncogenic allele of H-ras) results in direct tumorigenic conversion of normal human epithelial and fibroblast cells. These results demonstrate that disruption of the intracellular pathways regulated by large-T, oncogenic ras and telomerase suffices to create a human tumor cell.
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            Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation.

            It has been 30 years since a 'new' leukaemia termed adult T-cell leukaemia (ATL) was described in Japan, and more than 25 years since the isolation of the retrovirus, human T-cell leukaemia virus type 1 (HTLV-1), that causes this disease. We discuss HTLV-1 infectivity and how the HTLV-1 Tax oncoprotein initiates transformation by creating a cellular environment favouring aneuploidy and clastogenic DNA damage. We also explore the contribution of a newly discovered protein and RNA on the HTLV-1 minus strand, HTLV-1 basic leucine zipper factor (HBZ), to the maintenance of virus-induced leukaemia.
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              CD28-mediated co-stimulation: a quantitative support for TCR signalling.

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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                6 February 2018
                22 January 2018
                22 January 2018
                : 115
                : 6
                : E1269-E1278
                Affiliations
                aLaboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University , Kyoto 606-8507, Japan;
                bMathematical Biology Laboratory, Department of Biology, Faculty of Sciences, Kyushu University , Fukuoka 819-0395, Japan;
                cPrecursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency , Saitama 332-0012, Japan;
                dCore Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency , Saitama 332-0012, Japan;
                eInstitute of Industrial Sciences, The University of Tokyo , Tokyo 153-8505, Japan;
                fSchool of Medicine, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University , Ishikawa 920-8640, Japan;
                gDepartment of Hematology, Rheumatology and Infectious Diseases, Kumamoto University School of Medicine , Kumamoto 860-8556, Japan
                Author notes
                1To whom correspondence may be addressed. Email: jyasunag@ 123456infront.kyoto-u.ac.jp or mamatsu@ 123456kumamoto-u.ac.jp .

                Edited by Robert C. Gallo, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, and approved December 20, 2017 (received for review September 7, 2017)

                Author contributions: M. Mahgoub, J.-i.Y. and M. Matsuoka designed research; M. Mahgoub, J.-i.Y., S.I., S.N., K.S., and M. Matsuoka performed research; M. Mahgoub, J.-i.Y., S.I., S.N., Y.K., K.S., and M. Matsuoka analyzed data; and M. Mahgoub, J.-i.Y., S.I., S.N., and M. Matsuoka wrote the paper.

                Article
                201715724
                10.1073/pnas.1715724115
                5819419
                29358408
                Copyright © 2018 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                Page count
                Pages: 10
                Product
                Funding
                Funded by: MEXT | Japan Society for the Promotion of Science (JSPS) 501100001691
                Award ID: JP16H05336
                Funded by: MEXT | Japan Society for the Promotion of Science (JSPS) 501100001691
                Award ID: JP17K07166
                Funded by: Japan Agency for Medical Research and Development (AMED) 100009619
                Award ID: 17cm0106306h0002
                Award ID: 17fk0108227h0002
                Funded by: Japan Agency for Medical Research and Development (AMED) 100009619
                Award ID: 17cm0106306h0002
                Award ID: 17fk0108227h0002
                Funded by: Yasuda Memorial Medical Foundation (Yasuda Medical Foundation) 501100008673
                Award ID: NA
                Funded by: Japan Society for the Promotion of Science London (JSPS London) 501100000646
                Award ID: Core-to-Core Program A
                Funded by: Princess Takamatsu Cancer Research Fund 501100008886
                Award ID: NA
                Funded by: Japan Agency for Medical Research and Development (AMED) 100009619
                Award ID: 17fm0208006h0001
                Award ID: 17fm0208019h0101
                Award ID: 17fm0208014h0001
                Funded by: MEXT | JST | Precursory Research for Embryonic Science and Technology (PRESTO) 501100009023
                Award ID: NA
                Funded by: MEXT | JST | Core Research for Evolutional Science and Technology (CREST) 501100003382
                Award ID: NA
                Categories
                PNAS Plus
                Biological Sciences
                Microbiology
                PNAS Plus

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