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Journal of Virology, June 2007, p. 5714-5723, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02511-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Preferential Selection of Human T-Cell Leukemia Virus Type 1 Provirus Lacking the 5' Long Terminal Repeat during Oncogenesis{triangledown}

Maki Miyazaki,1 Jun-Ichirou Yasunaga,1 Yuko Taniguchi,1 Sadahiro Tamiya,2 Tatsutoshi Nakahata,3 and Masao Matsuoka1*

Laboratory of Virus Immunology, Institute for Virus Research,1 Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto 606-8507,3 Department of Hematology and Department of Infectious Diseases, Graduate School of Medicine, Kumamoto University, Kumamoto 860-8556, Japan2

Received 15 November 2006/ Accepted 27 February 2007

In adult T-cell leukemia (ATL) cells, a defective human T-cell leukemia virus type 1 (HTLV-1) provirus lacking the 5' long terminal repeat (LTR), designated type 2 defective provirus, is frequently observed. To investigate the mechanism underlying the generation of the defective provirus, we sequenced HTLV-1 provirus integration sites from cases of ATL. In HTLV-1 proviruses retaining both LTRs, 6-bp repeat sequences were adjacent to the 5' and 3' LTRs. In 8 of 12 cases with type 2 defective provirus, 6-bp repeats were identified at both ends. In five of these cases, a short repeat was bound to CA dinucleotides of the pol and env genes at the 5' end, suggesting that these type 2 defective proviruses were formed before integration. In four cases lacking the 6-bp repeat, short (6- to 26-bp) deletions in the host genome were identified, indicating that these defective proviruses were generated after integration. Quantification indicated frequencies of type 2 defective provirus of less than 3.9% for two carriers, which are much lower than those seen for ATL cases (27.8%). In type 2 defective proviruses, the second exons of the tax, rex, and p30 genes were frequently deleted, leaving Tax unable to activate NF-{kappa}B and CREB pathways. The HTLV-1 bZIP factor gene, located on the minus strand, is expressed in ATL cells with this defective provirus, and its coding sequences are intact, suggesting its significance in oncogenesis.


* Corresponding author. Mailing address: Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Shogoin Kawara-cho 53, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 81-75-751-4048. Fax: 81-75-751-4049. E-mail: mmatsuok{at}virus.kyoto-u.ac.jp

{triangledown} Published ahead of print on 7 March 2007.


Journal of Virology, June 2007, p. 5714-5723, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02511-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.




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