Strict Control of Human Immunodeficiency Virus Type 1 Replication by a Genetic Switch: Tet for Tat
Open accessAbstract
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.
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In the presence of dox, rtTA binds to the tetO-LTR promoter and activates viral transcription, so HIV-rtTA replication can be controlled by the administration of dox.
“In the presence of dox, rtTA will bind to the tetO-LTR promoter and activate viral transcription. HIV-rtTA replication can thus be controlled by the administration of dox (Fig. 3C).”
From Tet-On Systems For Doxycycline-inducible Gene Expression (2016) · cites this paper as [42]
We used the Tet-On system to generate an HIV-1 variant that replicates exclusively in the presence of dox.
“We used the Tet-On system to generate an HIV-1 variant that replicates exclusively in the presence of dox [42].”
From Tet-On Systems For Doxycycline-inducible Gene Expression (2016) · cites this paper as [42]
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“To improve the safety of live-attenuated HIV vaccine candidates, we and others previously presented a conditionally replicating HIV variant, with replication that can be switched on and off at will by the administration and removal of an exogenous effector, respectively [42, 52-55].”
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Self-citationP-TEFb Kinase Complex Phosphorylates Histone H1 to Regulate Expression of Cellular and HIV-1 Genes
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Gene Therapy of HIV-1 Infection Using Lentiviral Vectors Expressing Anti-HIV-1 Genes
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Self-citationImproved single-chain transactivators of the Tet-On gene expression system
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Self-citationNo vaccine against HIV yet--are we not perfectly equipped?
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Self-citationVaccination against Toxoplasmosis
Roberts, C. W., McLeod, R. L., Henriquez, F. L., & Alexander, J. K. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-396481-6.00026-x · Cited by 20 · see citing works
Replicating viral vectors as HIV vaccines
Koff, W. C., Parks, C. L., Berkhout, B., Ackland, J., Noble, S., & Gust, I. D. (2008) · Biologicals · doi:10.1016/j.biologicals.2008.04.004 · Cited by 19 · see citing works
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Self-citationHIV-1 evolution: frustrating therapies, but disclosing molecular mechanisms
Das, A. T., & Berkhout, B. (2010) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2010.0072 · Cited by 17 · see citing works
Self-citationConditional live virus as a novel approach towards a safe live attenuated HIV vaccine
Das, A. T., Zhou, X., Vink, M. A., Klaver, B., & Berkhout, B. (2002) · Expert Review of Vaccines · doi:10.1586/14760584.1.3.293 · Cited by 17 · see citing works
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Self-citationVaccination Against Toxoplasmosis: Current Status and Future Prospects
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Impact of Nuclear Export Pathway on Cytoplasmic HIV-1 RNA Transport Mechanism and Distribution
Chen, J., Umunnakwe, C. N., Sun, D., Nikolaitchik, O. A., Pathak, V. K., Berkhout, B., Das, A. T., & Hu, W.-S. (2020) · mBio · doi:10.1128/mbio.01578-20 · Cited by 12 · see citing works
Self-citationNovel vaccine delivery systems: solutions to HIV vaccine dilemmas?
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Self-citationVirus Evolution as a Tool to Study HIV-1 Biology
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Self-citationBeyond retrovirus infection: HIV meets gene therapy
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HIV vaccine: it may take two to tango, but no party time yet
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Possible Applications for Replicating Hiv-1 Vectors
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Self-citationTat has a dual role in simian immunodeficiency virus transcription
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Conditionally replicating HIV and SIV variants
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Self-citationResearch Strategies for Treatment of Nanobacteria
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A Conditionally Replicating Human Immunodeficiency Virus in BRG-HIS Mice
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Vaccine Approaches for Protection Against HIV
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Etude des mécanismes contrôlant la spécificité d'encapsidation des ARN dans le VIH-1
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- Authors
- Verhoef, K., Marzio, G., Hillen, W., Bujard, H., & Berkhout, B.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Heidelberg University (DE)
- ORCID
- Berkhout, Ben
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2001-01-15
- Volume
- 75
- Issue
- 2
- Pages
- 979-987
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC113994
- OpenAlex
- W2087430988
- Cited by
- 88
- References
- 55
- Citations by year
- 2020: 2 · 2017: 1 · 2016: 3 · 2015: 3 · 2014: 1 · 2013: 2 · 2012: 5
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- KWF Kankerbestrijding
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- HIV-1, Tet-On system, doxycycline-inducible expression, replication control, primary T cells
- MeSH terms
- Bacterial Proteins, Cell Line, Chemoreceptor Cells, Escherichia coli, Humans, Membrane Proteins, Receptors, Cell Surface, Repressor Proteins, T-Lymphocytes, Transfection, Virus Replication, HIV-1, Transcriptional Activation, Gene Products, tat, Gene Expression Regulation, Viral, Mutagenesis, Insertional, Gene Deletion, Escherichia coli Proteins, tat Gene Products, Human Immunodeficiency Virus
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