The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index.
LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration
Open accessAbstract
LEDGF/p75 directly interacts with lentiviral integrase proteins and can modulate their enzymatic activities and chromosomal association. A novel genetic knockout model was established that allowed us for the first time to analyze HIV-1 integration in the absence of LEDGF/p75 protein. Supporting a crucial role for the cofactor in viral replication, HIV-1 vector integration and reporter gene expression were significantly reduced in LEDGF-null cells. Yet, integrase processed the viral cDNA termini normally and maintained its local target DNA sequence preference during integration. Preintegration complexes extracted from knockout cells moreover supported normal levels of DNA strand transfer activity in vitro. In contrast, HIV-1 lost its strong bias toward integrating into transcription units, displaying instead increased affinity for promoter regions and CpG islands. Our results reveal LEDGF/p75 as a critical targeting factor, commandeering lentiviruses from promoter- and/or CpG island-proximal pathways that are favored by other members of Retroviridae . Akin to yeast retrotransposons, disrupting the lentiviral targeting mechanism significantly perturbs overall integration.
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“The genic proviruses that did form under these conditions uncharacteristically congregated around transcription start sites87,99–101.”
From Structure and function of retroviral integrase (2022) · cites this paper as [99]
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“Knockout of the PSIP1 gene, which encodes for LEDGF/p75, similarly suppressed levels of vDNA integration in cells several fold98,99.”
From Structure and function of retroviral integrase (2022) · cites this paper as [99]
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“Alterations that disrupted LEDGF/p75 binding to chromatin or IN ablated its cofactor function during HIV-1 infection99,103,112.”
From Structure and function of retroviral integrase (2022) · cites this paper as [99]
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“However, while LEDGF/p75 is critical, it is not strictly essential for HIV-1 integration and replication. This assertion is supported by the fact that HIV-1 was able to replicate, albeit at a much-reduced level, in LEDGF knockdown cells, and the replication could be restored upon expression of LEDGF/p75 (Llano et al. 2006, Shun et al. 2007).”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Shun et al. 2007
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Citations
Cites
HIV-1 Integration in the Human Genome Favors Active Genes and Local Hotspots
Schröder, A. R. W., Shinn, P., Chen, H., Berry, C., Ecker, J. R., & Bushman, F. (2002) · Cell · doi:10.1016/s0092-8674(02)00864-4 · Cited by 1,832
Transcription Start Regions in the Human Genome Are Favored Targets for MLV Integration
Wu, X., Li, Y., Crise, B., & Burgess, S. M. (2003) · Science · doi:10.1126/science.1083413 · Cited by 1,305
Retroviral DNA Integration: ASLV, HIV, and MLV Show Distinct Target Site Preferences
Mitchell, R., Beitzel, B. F., Schröder, A. R. W., Shinn, P., Chen, H., Berry, C. C., Ecker, J. R., & Bushman, F. D. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020234 · Cited by 1,002
Deininger, P. L., & Batzer, M. A. (1999) · Molecular Genetics and Metabolism · doi:10.1006/mgme.1999.2864 · Cited by 911
Inducible gene targeting in mice using the Cre/lox system.
Sauer, B. (1998) · Methods · doi:10.1006/meth.1998.0593 · Cited by 858
HIV-1 Integrase Forms Stable Tetramers and Associates with LEDGF/p75 Protein in Human Cells
Cherepanov, P., Maertens, G., Proost, P., Devreese, B., Van Beeumen, J., Engelborghs, Y., De Clercq, E., & Debyser, Z. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209278200 · Cited by 704
Self-citationA role for LEDGF/p75 in targeting HIV DNA integration
Ciuffi, A., Llano, M., Poeschla, E., Hoffmann, C., Leipzig, J., Shinn, P., Ecker, J. R., & Bushman, F. (2005) · Nature Medicine · doi:10.1038/nm1329 · Cited by 658
HIV-1 DNA integration: Mechanism of viral DNA cleavage and DNA strand transfer
Engelman, A., Mizuuchi, K., & Craigie, R. (1991) · Cell · doi:10.1016/0092-8674(91)90297-c · Cited by 655
Self-citationAn essential role for LEDGF/p75 in HIV integration
Llano, M., Saenz, D. T., Meehan, A., Wongthida, P., Peretz, M., Walker, W. H., Teo, W., & Poeschla, E. M. (2006) · Science · doi:10.1126/science.1132319 · Cited by 537
Breaking barriers to transcription elongation
Saunders, A., Core, L. J., & Lis, J. T. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1981 · Cited by 525
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Menin Critically Links MLL Proteins with LEDGF on Cancer-Associated Target Genes
Yokoyama, A., & Cleary, M. L. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.05.003 · Cited by 551
Yan, N., Regalado-Magdos, A. D., Stiggelbout, B., Lee‐Kirsch, M. A., & Lieberman, J. (2010) · Nature Immunology · doi:10.1038/ni.1941 · Cited by 522
Christ, F., Voet, A., Marchand, A., Nicolet, S., Desimmie, B. A., Marchand, D., Bardiot, D., Van der Veken, N. J., Van Remoortel, B., Strelkov, S. V., et al. (2010) · Nature Chemical Biology · doi:10.1038/nchembio.370 · Cited by 479
H3K4me3 Interactions with TAF3 Regulate Preinitiation Complex Assembly and Selective Gene Activation
Lauberth, S. M., Nakayama, T., Wu, X., Ferris, A. L., Tang, Z., Hughes, S. H., & Roeder, R. G. (2013) · Cell · doi:10.1016/j.cell.2013.01.052 · Cited by 473
Self-citationHost Cell Factors in HIV Replication: Meta-Analysis of Genome-Wide Studies
Bushman, F. D., Malani, N., Fernandes, J. D., D’Orso, I., Cagney, G., Diamond, T. L., Zhou, H., Hazuda, D. J., Espeseth, A. S., König, R., et al. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000437 · Cited by 464
Metadata
- Authors
- Shun, M.-C., Raghavendra, N. K., Vandegraaff, N., Daigle, J. E., Hughes, S., Kellam, P., Cherepanov, P., & Engelman, A.
- Affiliations
- Harvard University (US)
- Imperial College London (GB)
- University College London (GB)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-07-15
- Volume
- 21
- Issue
- 14
- Pages
- 1767-1778
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1920171
- OpenAlex
- W2106494657
- Cited by
- 467
- References
- 61
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 11 · 2023: 13 · 2022: 26 · 2021: 24 · 2020: 13 · 2019: 17 · 2018: 18 · 2017: 24 · 2016: 26 · 2015: 32 · 2014: 37 · 2013: 26 · 2012: 32
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institutes of Health
- Medical Research Council
- National Institute of Allergy and Infectious Diseases (AI39394, R01AI039394, R37AI039394)
- 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
- LEDGF/p75, HIV-1 integration, preintegration complex, CpG islands, DNA strand transfer, retroviral replication
- MeSH terms
- Animals, Base Sequence, Binding Sites, Cell Line, DNA, Humans, Leukemia Virus, Murine, Promoter Regions, Genetic, Transcription Factors, HIV-1, Consensus Sequence, Virus Integration, Gene Deletion, CpG Islands, Integrases, Intercellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, In Vitro Techniques
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