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Journal of Virology, September 2002, p. 9389-9397, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9389-9397.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

5'-Long Terminal Repeat-Selective CpG Methylation of Latent Human T-Cell Leukemia Virus Type 1 Provirus In Vitro and In Vivo

Tsukasa Koiwa,1 Akiko Hamano-Usami,1 Takaomi Ishida,1 Akihiko Okayama,2 Kazunari Yamaguchi,3 Shimeru Kamihira,4 and Toshiki Watanabe1*

Division of Pathology, Department of Cancer Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639,1 Department of Internal Medicine, Miyazaki Medical College, Miyazaki 889-1601,2 Blood Transfusion Service, Kumamoto University, Kumamoto 860-8556,3 Department of Laboratory Medicine, Nagasaki University, Nagasaki 852-8523, Japan4

Received 25 March 2002/ Accepted 5 June 2002

CpG methylation of the human T-cell leukemia virus type 1 (HTLV-1) long terminal repeat (LTR) has been implicated in proviral latency, but there is presently little information available regarding the pattern of LTR methylation and its effect on viral gene expression. To gain insight into the mechanisms of HTLV-1 latency, we have studied methylation of individual CpG sites in the U3-R region of the integrated proviral LTR by using bisulfite genomic sequencing methods. Surprisingly, our results reveal selective hypermethylation of the 5' LTR and accompanying hypomethylation of the 3' LTR in both latently infected cell lines and adult T-cell leukemia (ATL) cells having a complete provirus. Moreover, we observed a lack of CpG methylation in the LTRs of 5'-defective proviruses recovered from ATL samples, which is consistent with the selective hypomethylation of the 3' LTR. Thus, the integrated HTLV-1 provirus in these carriers appears to be hypermethylated in the 5' LTR and hypomethylated in the 3' LTR. These results, together with the observation that proviral gene expression is reactivated by 5-azacytidine in latently infected cell lines, indicate that selective hypermethylation of the HTLV-1 5' LTR is common both in vivo and in vitro. Thus, hypermethylation of the 5' LTR appears to be an important mechanism by which HTLV-1 gene expression is repressed during viral latency.

* Corresponding author. Mailing address: Division of Pathology, Department of Cancer Research, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5298. Fax: 81-3-5449-5418. E-mail: tnabe{at}ims.u-tokyo.ac.jp.

Journal of Virology, September 2002, p. 9389-9397, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9389-9397.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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