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Title: Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells
Authors: Mahgoub, Mohamed
Yasunaga, Jun-ichirou
Iwami, Shingo
Nakaoka, Shinji
Koizumi, Yoshiki
Shimura, Kazuya  kyouindb  KAKEN_id  orcid (unconfirmed)
Matsuoka, Masao
Author's alias: 安永, 純一朗
岩見, 真吾
松岡, 雅雄
Keywords: HTLV-1
adult T-cell leukemia–lymphoma
computational simulation
Issue Date: 22-Jan-2018
Publisher: National Academy of Sciences
Journal title: Proceedings of the National Academy of Sciences
Volume: 115
Issue: 6
Start page: E1269
End page: E1278
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.
Description: ヒトT細胞白血病ウイルス1型 (HTLV-1)の新しい感染維持機構を解明 --HTLV-1による白血病の発症機序解明と発症予防への応用に期待--. 京都大学プレスリリース. 2018-01-25.
Rights: This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
DOI(Published Version): 10.1073/pnas.1715724115
PubMed ID: 29358408
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