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Journal of Virology, January 2001, p. 979-987, Vol. 75, No. 2
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.2.979-987.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Strict Control of Human Immunodeficiency Virus Type 1 Replication by a Genetic Switch: Tet for Tat

Koen Verhoef,1,dagger Giuseppe Marzio,1 Wolfgang Hillen,2 Hermann Bujard,3 and Ben Berkhout1,*

Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands,1 and Friedrich-Alexander University, Erlangen,2 and Zentrum für Molekulare Biologie, University of Heidelberg, Heidelberg,3 Germany

Received 25 July 2000/Accepted 11 October 2000

Live-attenuated human immunodeficiency virus type 1 (HIV-1) variants have shown great promise as AIDS vaccines, but continued replication can lead to the selection of faster-replicating variants that are pathogenic. We therefore designed HIV-1 genomes that replicate exclusively upon addition of the nontoxic effector doxycycline (dox). This was achieved by replacement of the viral TAR-Tat system for transcriptional activation by the Escherichia coli-derived Tet system for inducible gene expression. These designer "HIV-rtTA" viruses replicate in a strictly dox-dependent manner both in a T-cell line and in primary blood cells, and the rate of replication can be fine-tuned by simple variation of the dox concentration. These HIV-rtTA viruses provide a tool to perform genetics, e.g., selection and optimization experiments, with the E. coli-derived Tet reagents in a eukaryotic background. Furthermore, such viruses may represent improved vaccine candidates because their replication can be turned on and off at will.

* Corresponding author. Mailing address: Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Phone: (31-20) 566-5822. Fax: (31-20) 566-9064. E-mail: b.berkhout{at}amc.uva.nl.

dagger Present address: Department of Biochemistry, University of Oxford, Oxford, England.

Journal of Virology, January 2001, p. 979-987, Vol. 75, No. 2
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.2.979-987.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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