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Journal of Virology, May 2000, p. 4679-4687, Vol. 74, No. 10
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The cHS4 Insulator Increases the Probability of Retroviral Expression at Random Chromosomal Integration Sites

Stefano Rivella, John A. Callegari, Chad May, Cui Wen Tan, and Michel Sadelain*

Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Received 5 October 1999/Accepted 4 February 2000

Retroviruses are highly susceptible to transcriptional silencing and position effects imparted by chromosomal sequences at their integration site. These phenomena hamper the use of recombinant retroviruses as stable gene delivery vectors. As insulators are able to block promoter-enhancer interactions and reduce position effects in some transgenic animals, we examined the effect of an insulator on the expression and structure of randomly integrated recombinant retroviruses. We used the cHS4 element, an insulator from the chicken beta -like globin gene cluster, which has been shown to reduce position effects in transgenic Drosophila. A large panel of mouse erythroleukemia cells that bear a single copy of integrated recombinant retroviruses was generated without using drug selection. We show that the cHS4 increases the probability that integrated proviruses will express and dramatically decreases the level of de novo methylation of the 5' long terminal repeat. These findings support a primary role of methylation in the silencing of retroviruses and suggest that cHS4 could be useful in gene therapy applications to overcome silencing of retroviral vectors.

* Corresponding author. Mailing address: Department of Human Genetics, Box 182, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: (212) 639-6190. Fax: (917) 432-2340. E-mail: m-sadelain{at}ski.mskcc.org.

Journal of Virology, May 2000, p. 4679-4687, Vol. 74, No. 10
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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