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

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...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS Jg. 115; H. 6; S. E1269
Hauptverfasser: Mahgoub, Mohamed, Yasunaga, Jun-Ichirou, Iwami, Shingo, Nakaoka, Shinji, Koizumi, Yoshiki, Shimura, Kazuya, Matsuoka, Masao
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 06.02.2018
Schlagworte:
Gene Expression Regulation, Viral
Gene Products, tax - genetics
Gene Products, tax - metabolism
HTLV-I Infections - genetics
HTLV-I Infections - metabolism
HTLV-I Infections - virology
Human T-lymphotropic virus 1 - pathogenicity
Humans
Leukemia-Lymphoma, Adult T-Cell - genetics
Leukemia-Lymphoma, Adult T-Cell - metabolism
Leukemia-Lymphoma, Adult T-Cell - virology
Single-Cell Analysis
T-Lymphocytes - virology
Virus Activation
Virus Replication
HBZ
computational simulation
HTLV-1
Tax
adult T-cell leukemia–lymphoma
ISSN:1091-6490, 1091-6490
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1715724115