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Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):E1269-E1278. doi: 10.1073/pnas.1715724115. Epub 2018 Jan 22.

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

Author information

1
Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
2
Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan; jyasunag@infront.kyoto-u.ac.jp mamatsu@kumamoto-u.ac.jp.
3
Mathematical Biology Laboratory, Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 819-0395, Japan.
4
Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama 332-0012, Japan.
5
Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan.
6
Institute of Industrial Sciences, The University of Tokyo, Tokyo 153-8505, Japan.
7
School of Medicine, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa 920-8640, Japan.
8
Department of Hematology, Rheumatology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan.

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.

KEYWORDS:

HBZ; HTLV-1; Tax; adult T-cell leukemia–lymphoma; computational simulation

PMID:
29358408
PMCID:
PMC5819419
DOI:
10.1073/pnas.1715724115
[Indexed for MEDLINE]
Free PMC Article

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