title: Strict control of human immunodeficiency virus type 1 replication by a genetic switch: Tet for Tat.
abstract: 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.
authors.affiliation: Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Verhoef
authors.forename: G
authors.initials: G
authors.lastname: Marzio
authors.forename: W
authors.initials: W
authors.lastname: Hillen
authors.forename: H
authors.initials: H
authors.lastname: Bujard
authors.forename: B
authors.initials: B
authors.lastname: Berkhout
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002628:Chemoreceptor Cells; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins; D017353:Gene Deletion; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016254:Mutagenesis, Insertional; D011956:Receptors, Cell Surface; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000821:virology; D015533:Transcriptional Activation; D014162:Transfection; D014779:Virus Replication; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D015696:Gene Products, tat; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C057331:Tar protein, E coli; D054322:tat Gene Products, Human Immunodeficiency Virus; C034811:tetracycline resistance-encoding transposon repressor protein