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Cited by 241Virus-based gene therapy researchHIV Research and TreatmentHIV/AIDS drug development and treatment

Role of PSIP1/LEDGF/p75 in Lentiviral Infectivity and Integration Targeting

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Marshall, Heather M., Ronen, Keshet, Berry, Charles, Llano, Manuel, Sutherland, Heidi, Saenz, Dyana, Bickmore, Wendy, Poeschla, Eric +1 more·2007·PLoS ONE
DOI 10.1371/journal.pone.0001340PMC PMC2129110
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Abstract

BACKGROUND: To replicate, lentiviruses such as HIV must integrate DNA copies of their RNA genomes into host cell chromosomes. Lentiviral integration is favored in active transcription units, which allows efficient viral gene expression after integration, but the mechanisms directing integration targeting are incompletely understood. A cellular protein, PSIP1/LEDGF/p75, binds tightly to the lentiviral-encoded integrase protein (IN), and has been reported to be important for HIV infectivity and integration targeting. METHODOLOGY: Here we report studies of lentiviral integration targeting in 1) human cells with intensified RNAi knockdowns of PSIP1/LEDGF/p75, and 2) murine cells with homozygous gene trap mutations in the PSIP1/LEDGF/p75 locus. Infections with vectors derived from equine infections anemia virus (EIAV) and HIV were compared. Integration acceptor sites were analyzed by DNA bar coding and pyrosequencing. CONCLUSIONS/SIGNIFICANCE: In both PSIP1/LEDGF/p75-depleted cell lines, reductions were seen in lentiviral infectivity compared to controls. For the human cells, integration was reduced in transcription units in the knockdowns, and this reduction was greater than in our previous studies of human cells less completely depleted for PSIP1/LEDGF/p75. For the homozygous mutant mouse cells, similar reductions in integration in transcription units were seen, paralleling a previous study of a different mutant mouse line. Integration did not become random, however-integration in transcription units in both cell types was still favored, though to a reduced degree. New trends also appeared, including favored integration near CpG islands. In addition, we carried out a bioinformatic study of 15 HIV integration site data sets in different cell types, which showed that the frequency of integration in transcription units was correlated with the cell-type specific levels of PSIP1/LEDGF/p75 expression.

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  • Loss of PSIP1, the gene encoding LEDGF/p75, reduced viral DNA integration in cells by several fold.

    “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 [98]

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References 66 · Cited by 241

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Authors
Marshall, H. M., Ronen, K., Berry, C., Llano, M., Sutherland, H., Saenz, D., Bickmore, W., Poeschla, E., & Bushman, F. D.
Affiliations
  • University of Pennsylvania (US)
  • University of California San Diego (US)
  • Mayo Clinic (US)
  • MRC Human Genetics Unit (GB)
Corresponding author
Bushman, Frederic D.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2007-12-19
Volume
2
Issue
12
Pages
e1340
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0001340
PMC
PMC2129110
OpenAlex
W2078738195
Cited by
241
References
66
Citations by year
2026: 2 · 2025: 6 · 2024: 4 · 2023: 5 · 2022: 17 · 2021: 7 · 2020: 4 · 2019: 6 · 2018: 9 · 2017: 5 · 2016: 16 · 2015: 11 · 2014: 20 · 2013: 16 · 2012: 22
FWCI
11.65
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Griffith Research Online (submittedVersion, cc-by)
Funders
  • University of Pennsylvania
  • James B. Pendleton Charitable Trust
  • National Institutes of Health (AI66290, AI007632)
  • U.S. Public Health Service (T32 07229-33)
  • University of North Carolina at Chapel Hill
  • National Institute of Allergy and Infectious Diseases (AI 47536, AI007632, T32AI007632, AI52845, R01AI077344, R01AI047536, R21AI047536, AI66290, U19AI066290, R01AI052845)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
Keywords
lentiviral integration, HIV infectivity, integrase, equine infectious anemia virus, transcription units, CpG islands, integration site mapping, RNAi knockdown, gene trap mice, cell type-specific gene expression
MeSH terms
Animals, Cell Line, Infectious Anemia Virus, Equine, HIV, Humans, Transcription Factors, Virulence, Consensus Sequence, Virus Integration, Adaptor Proteins, Signal Transducing, Mice

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