Role of PSIP1/LEDGF/p75 in lentiviral infectivity and integration targeting
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 in...
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| description | 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.
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.
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. |
| doi_str_mv | 10.1371/journal.pone.0001340 |
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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.
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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0001340</identifier><identifier>PMID: 18092005</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adaptor Proteins, Signal Transducing - physiology ; Analysis ; Anemia ; Animals ; Cell Line ; Cell lines ; Cells (Biology) ; Cellular proteins ; Chromosomes ; Consensus Sequence ; CpG islands ; Deoxyribonucleic acid ; DNA ; Fibroblasts ; Gene expression ; Gene therapy ; Genes ; Genetic aspects ; Genetics and Genomics/Gene Therapy ; Genomes ; Genomics ; Health aspects ; HIV ; HIV - genetics ; HIV - pathogenicity ; Human immunodeficiency virus ; Humans ; Infection ; Infections ; Infectious Anemia Virus, Equine - genetics ; Infectious Anemia Virus, Equine - pathogenicity ; Infectivity ; Integrase ; Integration ; Medical research ; Mice ; Microbiology ; Microbiology/Cellular Microbiology and Pathogenesis ; Mutation ; Preventive medicine ; Protein binding ; Proteins ; Ribonucleic acid ; RNA ; RNA-mediated interference ; Rodents ; Transcription ; Transcription (Genetics) ; Transcription Factors - physiology ; Vectors ; Virology ; Virology/Effects of Virus Infection on Host Gene Expression ; Virology/Immunodeficiency Viruses ; Virology/Mechanisms of Resistance and Susceptibility, including Host Genetics ; Virulence - physiology ; Virus Integration - physiology ; Viruses</subject><ispartof>PloS one, 2007-12, Vol.2 (12), p.e1340-e1340</ispartof><rights>COPYRIGHT 2007 Public Library of Science</rights><rights>2007 Marshall et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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.
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.
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.</description><subject>Adaptor Proteins, Signal Transducing - physiology</subject><subject>Analysis</subject><subject>Anemia</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Cell lines</subject><subject>Cells (Biology)</subject><subject>Cellular proteins</subject><subject>Chromosomes</subject><subject>Consensus Sequence</subject><subject>CpG islands</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Fibroblasts</subject><subject>Gene expression</subject><subject>Gene therapy</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetics and Genomics/Gene Therapy</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Health aspects</subject><subject>HIV</subject><subject>HIV - genetics</subject><subject>HIV - pathogenicity</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Infection</subject><subject>Infections</subject><subject>Infectious Anemia Virus, Equine - genetics</subject><subject>Infectious Anemia Virus, Equine - pathogenicity</subject><subject>Infectivity</subject><subject>Integrase</subject><subject>Integration</subject><subject>Medical research</subject><subject>Mice</subject><subject>Microbiology</subject><subject>Microbiology/Cellular Microbiology and Pathogenesis</subject><subject>Mutation</subject><subject>Preventive medicine</subject><subject>Protein binding</subject><subject>Proteins</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA-mediated interference</subject><subject>Rodents</subject><subject>Transcription</subject><subject>Transcription (Genetics)</subject><subject>Transcription Factors - physiology</subject><subject>Vectors</subject><subject>Virology</subject><subject>Virology/Effects of Virus Infection on Host Gene Expression</subject><subject>Virology/Immunodeficiency Viruses</subject><subject>Virology/Mechanisms of Resistance and Susceptibility, including Host Genetics</subject><subject>Virulence - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Marshall, Heather M</au><au>Ronen, Keshet</au><au>Berry, Charles</au><au>Llano, Manuel</au><au>Sutherland, Heidi</au><au>Saenz, Dyana</au><au>Bickmore, Wendy</au><au>Poeschla, Eric</au><au>Bushman, Frederic D</au><au>Fox, Debbie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of PSIP1/LEDGF/p75 in lentiviral infectivity and integration targeting</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2007-12-19</date><risdate>2007</risdate><volume>2</volume><issue>12</issue><spage>e1340</spage><epage>e1340</epage><pages>e1340-e1340</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.
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.
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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>18092005</pmid><doi>10.1371/journal.pone.0001340</doi><tpages>e1340</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1950341913 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adaptor Proteins, Signal Transducing - physiology Analysis Anemia Animals Cell Line Cell lines Cells (Biology) Cellular proteins Chromosomes Consensus Sequence CpG islands Deoxyribonucleic acid DNA Fibroblasts Gene expression Gene therapy Genes Genetic aspects Genetics and Genomics/Gene Therapy Genomes Genomics Health aspects HIV HIV - genetics HIV - pathogenicity Human immunodeficiency virus Humans Infection Infections Infectious Anemia Virus, Equine - genetics Infectious Anemia Virus, Equine - pathogenicity Infectivity Integrase Integration Medical research Mice Microbiology Microbiology/Cellular Microbiology and Pathogenesis Mutation Preventive medicine Protein binding Proteins Ribonucleic acid RNA RNA-mediated interference Rodents Transcription Transcription (Genetics) Transcription Factors - physiology Vectors Virology Virology/Effects of Virus Infection on Host Gene Expression Virology/Immunodeficiency Viruses Virology/Mechanisms of Resistance and Susceptibility, including Host Genetics Virulence - physiology Virus Integration - physiology Viruses |
| title | Role of PSIP1/LEDGF/p75 in lentiviral infectivity and integration targeting |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-22T03%3A00%3A22IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Role%20of%20PSIP1/LEDGF/p75%20in%20lentiviral%20infectivity%20and%20integration%20targeting&rft.jtitle=PloS%20one&rft.au=Marshall,%20Heather%20M&rft.date=2007-12-19&rft.volume=2&rft.issue=12&rft.spage=e1340&rft.epage=e1340&rft.pages=e1340-e1340&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0001340&rft_dat=%3Cgale_plos_%3EA472231927%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1289134167&rft_id=info:pmid/18092005&rft_galeid=A472231927&rft_doaj_id=oai_doaj_org_article_7b9c02548d2e4f89a366f3065f81933b&rfr_iscdi=true |