E4 antibodies facilitate detection and type-assignment of active HPV infection in cervical disease
High-risk human papillomavirus (HPV) infections are the cause of nearly all cases of cervical cancer. Although the detection of HPV DNA has proved useful in cervical diagnosis, it does not necessarily predict disease presence or severity, and cannot conclusively identify the causative type when mult...
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| creator | Griffin, Heather Wu, Zhonglin Marnane, Rebecca Dewar, Vincent Molijn, Anco Quint, Wim Van Hoof, Christine Struyf, Frank Colau, Brigitte Jenkins, David Doorbar, John |
| description | High-risk human papillomavirus (HPV) infections are the cause of nearly all cases of cervical cancer. Although the detection of HPV DNA has proved useful in cervical diagnosis, it does not necessarily predict disease presence or severity, and cannot conclusively identify the causative type when multiple HPVs are present. Such limitations may be addressed using complementary approaches such as cytology, laser capture microscopy, and/or the use of infection biomarkers. One such infection biomarker is the HPV E4 protein, which is expressed at high level in cells that are supporting (or have supported) viral genome amplification. Its distribution in lesions has suggested a role in disease staging. Here we have examined whether type-specific E4 antibodies may also allow the identification and/or confirmation of causal HPV-type. To do this, type-specific polyclonal and monoclonal antibodies against three E4 proteins (HPV-16, -18, and -58) were generated and validated by ELISA and western blotting, and by immunohistochemistry (IHC) staining of epithelial rafts containing these individual HPV types. Type-specific detection of HPV and its associated disease was subsequently examined using formalin-fixed paraffin-embedded cervical intra-epithelial neoplasias (CIN, (n = 247)) and normal controls (n = 28). All koilocytotic CIN1 lesions showed type-specific E4 expression of their respective HPV types. Differences were noted amongst E4 expression patterns in CIN3. HPV-18 E4 was not detected in any of the 6 HPV-18 DNA-positive CIN3 lesions examined, whereas in HPV-16 and -58 CIN3, 28/37 (76%) and 5/9 (55.6%) expressed E4 respectively, usually in regions of epithelial differentiation. Our results demonstrate that type-specific E4 antibodies can be used to help establish causality, as may be required when multiple HPV types are detected. The unique characteristics of the E4 biomarker suggest a role in diagnosis and patient management particularly when used in combination. |
| doi_str_mv | 10.1371/journal.pone.0049974 |
| format | Article |
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Although the detection of HPV DNA has proved useful in cervical diagnosis, it does not necessarily predict disease presence or severity, and cannot conclusively identify the causative type when multiple HPVs are present. Such limitations may be addressed using complementary approaches such as cytology, laser capture microscopy, and/or the use of infection biomarkers. One such infection biomarker is the HPV E4 protein, which is expressed at high level in cells that are supporting (or have supported) viral genome amplification. Its distribution in lesions has suggested a role in disease staging. Here we have examined whether type-specific E4 antibodies may also allow the identification and/or confirmation of causal HPV-type. To do this, type-specific polyclonal and monoclonal antibodies against three E4 proteins (HPV-16, -18, and -58) were generated and validated by ELISA and western blotting, and by immunohistochemistry (IHC) staining of epithelial rafts containing these individual HPV types. Type-specific detection of HPV and its associated disease was subsequently examined using formalin-fixed paraffin-embedded cervical intra-epithelial neoplasias (CIN, (n = 247)) and normal controls (n = 28). All koilocytotic CIN1 lesions showed type-specific E4 expression of their respective HPV types. Differences were noted amongst E4 expression patterns in CIN3. HPV-18 E4 was not detected in any of the 6 HPV-18 DNA-positive CIN3 lesions examined, whereas in HPV-16 and -58 CIN3, 28/37 (76%) and 5/9 (55.6%) expressed E4 respectively, usually in regions of epithelial differentiation. Our results demonstrate that type-specific E4 antibodies can be used to help establish causality, as may be required when multiple HPV types are detected. The unique characteristics of the E4 biomarker suggest a role in diagnosis and patient management particularly when used in combination.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0049974</identifier><identifier>PMID: 23226504</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alphapapillomavirus - genetics ; Alphapapillomavirus - immunology ; Alphapapillomavirus - isolation & purification ; Amino Acid Sequence ; Animals ; Antibodies, Monoclonal - chemistry ; Antibodies, Monoclonal - immunology ; Bioindicators ; Biology ; Biomarkers ; Biopsy ; Blotting, Western ; Causality ; Cell division ; Cervical cancer ; Cervix ; Cytology ; Deoxyribonucleic acid ; Diagnosis ; DNA ; DNA, Viral - analysis ; E4 protein ; Enzyme-Linked Immunosorbent Assay ; Ethics ; Female ; Formaldehyde ; Genomes ; Genomics ; Health aspects ; Health risks ; Histology ; Human papillomavirus ; Humans ; Immunoglobulins ; Immunohistochemistry ; Infection ; Infections ; Kleter ; Laboratories ; Lesions ; Medical research ; Medical screening ; Medicine ; Mice ; Mice, Inbred BALB C ; Microscopy ; Molecular Sequence Data ; Monoclonal antibodies ; Papillomavirus infections ; Papillomavirus Infections - diagnosis ; Paraffin ; Proteins ; Rabbits ; Rafts ; Sequence Homology, Amino Acid ; Sexually transmitted diseases ; Studies ; Uterine Cervical Neoplasms - pathology ; Uterine Cervical Neoplasms - virology ; Viral infections ; Western blotting ; Womens health</subject><ispartof>PloS one, 2012-12, Vol.7 (12), p.e49974-e49974</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Griffin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012 Griffin et al 2012 Griffin et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-4dd9daab759fdc9be177c1820c35835ea94c5426a5b385313ca0256845415f453</citedby><cites>FETCH-LOGICAL-c758t-4dd9daab759fdc9be177c1820c35835ea94c5426a5b385313ca0256845415f453</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513315/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513315/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23226504$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Griffin, Heather</creatorcontrib><creatorcontrib>Wu, Zhonglin</creatorcontrib><creatorcontrib>Marnane, Rebecca</creatorcontrib><creatorcontrib>Dewar, Vincent</creatorcontrib><creatorcontrib>Molijn, Anco</creatorcontrib><creatorcontrib>Quint, Wim</creatorcontrib><creatorcontrib>Van Hoof, Christine</creatorcontrib><creatorcontrib>Struyf, Frank</creatorcontrib><creatorcontrib>Colau, Brigitte</creatorcontrib><creatorcontrib>Jenkins, David</creatorcontrib><creatorcontrib>Doorbar, John</creatorcontrib><title>E4 antibodies facilitate detection and type-assignment of active HPV infection in cervical disease</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>High-risk human papillomavirus (HPV) infections are the cause of nearly all cases of cervical cancer. Although the detection of HPV DNA has proved useful in cervical diagnosis, it does not necessarily predict disease presence or severity, and cannot conclusively identify the causative type when multiple HPVs are present. Such limitations may be addressed using complementary approaches such as cytology, laser capture microscopy, and/or the use of infection biomarkers. One such infection biomarker is the HPV E4 protein, which is expressed at high level in cells that are supporting (or have supported) viral genome amplification. Its distribution in lesions has suggested a role in disease staging. Here we have examined whether type-specific E4 antibodies may also allow the identification and/or confirmation of causal HPV-type. To do this, type-specific polyclonal and monoclonal antibodies against three E4 proteins (HPV-16, -18, and -58) were generated and validated by ELISA and western blotting, and by immunohistochemistry (IHC) staining of epithelial rafts containing these individual HPV types. Type-specific detection of HPV and its associated disease was subsequently examined using formalin-fixed paraffin-embedded cervical intra-epithelial neoplasias (CIN, (n = 247)) and normal controls (n = 28). All koilocytotic CIN1 lesions showed type-specific E4 expression of their respective HPV types. Differences were noted amongst E4 expression patterns in CIN3. HPV-18 E4 was not detected in any of the 6 HPV-18 DNA-positive CIN3 lesions examined, whereas in HPV-16 and -58 CIN3, 28/37 (76%) and 5/9 (55.6%) expressed E4 respectively, usually in regions of epithelial differentiation. Our results demonstrate that type-specific E4 antibodies can be used to help establish causality, as may be required when multiple HPV types are detected. The unique characteristics of the E4 biomarker suggest a role in diagnosis and patient management particularly when used in combination.</description><subject>Alphapapillomavirus - genetics</subject><subject>Alphapapillomavirus - immunology</subject><subject>Alphapapillomavirus - isolation & purification</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - chemistry</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Bioindicators</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Biopsy</subject><subject>Blotting, Western</subject><subject>Causality</subject><subject>Cell division</subject><subject>Cervical cancer</subject><subject>Cervix</subject><subject>Cytology</subject><subject>Deoxyribonucleic acid</subject><subject>Diagnosis</subject><subject>DNA</subject><subject>DNA, Viral - analysis</subject><subject>E4 protein</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Ethics</subject><subject>Female</subject><subject>Formaldehyde</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Health aspects</subject><subject>Health risks</subject><subject>Histology</subject><subject>Human papillomavirus</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Immunohistochemistry</subject><subject>Infection</subject><subject>Infections</subject><subject>Kleter</subject><subject>Laboratories</subject><subject>Lesions</subject><subject>Medical research</subject><subject>Medical screening</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Microscopy</subject><subject>Molecular Sequence Data</subject><subject>Monoclonal antibodies</subject><subject>Papillomavirus infections</subject><subject>Papillomavirus Infections - diagnosis</subject><subject>Paraffin</subject><subject>Proteins</subject><subject>Rabbits</subject><subject>Rafts</subject><subject>Sequence Homology, Amino Acid</subject><subject>Sexually transmitted diseases</subject><subject>Studies</subject><subject>Uterine Cervical Neoplasms - pathology</subject><subject>Uterine Cervical Neoplasms - virology</subject><subject>Viral infections</subject><subject>Western blotting</subject><subject>Womens health</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk99rFDEQxxdRbK3-B6ILgujDnfm52X0RSqn2oFDxR1_DbDJ7l7K3uW6yh_3vzXnbcit9kDwkZD7znclkJsteUzKnXNFPN37oO2jnG9_hnBBRVUo8yY5pxdmsYIQ_PTgfZS9CuCFE8rIonmdHjDNWSCKOs_pc5NBFV3vrMOQNGNe6CBFzixFNdL5LdpvHuw3OIAS37NbYxdw3OSTrFvOLb9e565qRdV1usN86A21uXUAI-DJ71kAb8NW4n2S_vpz_PLuYXV59XZydXs6MkmWcCWsrC1ArWTXWVDVSpQwtGTFcllwiVMJIwQqQNS8lp9wAYbIohRRUNkLyk-ztXnfT-qDH8gRNOSuUpIrviMWesB5u9KZ3a-jvtAen_174fqmhj860qCnSgvGiIrWqBG94KVApKWzTWMmU4knr8xhtqNdoTSpKD-1EdGrp3Eov_VZzSTmnu2Q-jAK9vx0wRL12wWDbQod-SHkzntImrCgT-u4f9PHXjdQS0gPSl_gU1-xE9alQilREiCJR80eotCyunUm91Lh0P3H4OHFITMTfcQlDCHrx4_v_s1fXU_b9AbtCaOMq-HbYtVGYgmIPmt6H0GPzUGRK9G4U7quhd6Ogx1FIbm8OP-jB6b73-R_hIQIV</recordid><startdate>20121203</startdate><enddate>20121203</enddate><creator>Griffin, Heather</creator><creator>Wu, Zhonglin</creator><creator>Marnane, Rebecca</creator><creator>Dewar, Vincent</creator><creator>Molijn, Anco</creator><creator>Quint, Wim</creator><creator>Van Hoof, Christine</creator><creator>Struyf, Frank</creator><creator>Colau, Brigitte</creator><creator>Jenkins, David</creator><creator>Doorbar, John</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20121203</creationdate><title>E4 antibodies facilitate detection and type-assignment of active HPV infection in cervical disease</title><author>Griffin, Heather ; Wu, Zhonglin ; Marnane, Rebecca ; Dewar, Vincent ; Molijn, Anco ; Quint, Wim ; Van Hoof, Christine ; Struyf, Frank ; Colau, Brigitte ; Jenkins, David ; Doorbar, John</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-4dd9daab759fdc9be177c1820c35835ea94c5426a5b385313ca0256845415f453</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Alphapapillomavirus - 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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>Griffin, Heather</au><au>Wu, Zhonglin</au><au>Marnane, Rebecca</au><au>Dewar, Vincent</au><au>Molijn, Anco</au><au>Quint, Wim</au><au>Van Hoof, Christine</au><au>Struyf, Frank</au><au>Colau, Brigitte</au><au>Jenkins, David</au><au>Doorbar, John</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>E4 antibodies facilitate detection and type-assignment of active HPV infection in cervical disease</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-12-03</date><risdate>2012</risdate><volume>7</volume><issue>12</issue><spage>e49974</spage><epage>e49974</epage><pages>e49974-e49974</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>High-risk human papillomavirus (HPV) infections are the cause of nearly all cases of cervical cancer. Although the detection of HPV DNA has proved useful in cervical diagnosis, it does not necessarily predict disease presence or severity, and cannot conclusively identify the causative type when multiple HPVs are present. Such limitations may be addressed using complementary approaches such as cytology, laser capture microscopy, and/or the use of infection biomarkers. One such infection biomarker is the HPV E4 protein, which is expressed at high level in cells that are supporting (or have supported) viral genome amplification. Its distribution in lesions has suggested a role in disease staging. Here we have examined whether type-specific E4 antibodies may also allow the identification and/or confirmation of causal HPV-type. To do this, type-specific polyclonal and monoclonal antibodies against three E4 proteins (HPV-16, -18, and -58) were generated and validated by ELISA and western blotting, and by immunohistochemistry (IHC) staining of epithelial rafts containing these individual HPV types. Type-specific detection of HPV and its associated disease was subsequently examined using formalin-fixed paraffin-embedded cervical intra-epithelial neoplasias (CIN, (n = 247)) and normal controls (n = 28). All koilocytotic CIN1 lesions showed type-specific E4 expression of their respective HPV types. Differences were noted amongst E4 expression patterns in CIN3. HPV-18 E4 was not detected in any of the 6 HPV-18 DNA-positive CIN3 lesions examined, whereas in HPV-16 and -58 CIN3, 28/37 (76%) and 5/9 (55.6%) expressed E4 respectively, usually in regions of epithelial differentiation. Our results demonstrate that type-specific E4 antibodies can be used to help establish causality, as may be required when multiple HPV types are detected. The unique characteristics of the E4 biomarker suggest a role in diagnosis and patient management particularly when used in combination.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23226504</pmid><doi>10.1371/journal.pone.0049974</doi><tpages>e49974</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-12, Vol.7 (12), p.e49974-e49974 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1326751735 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Alphapapillomavirus - genetics Alphapapillomavirus - immunology Alphapapillomavirus - isolation & purification Amino Acid Sequence Animals Antibodies, Monoclonal - chemistry Antibodies, Monoclonal - immunology Bioindicators Biology Biomarkers Biopsy Blotting, Western Causality Cell division Cervical cancer Cervix Cytology Deoxyribonucleic acid Diagnosis DNA DNA, Viral - analysis E4 protein Enzyme-Linked Immunosorbent Assay Ethics Female Formaldehyde Genomes Genomics Health aspects Health risks Histology Human papillomavirus Humans Immunoglobulins Immunohistochemistry Infection Infections Kleter Laboratories Lesions Medical research Medical screening Medicine Mice Mice, Inbred BALB C Microscopy Molecular Sequence Data Monoclonal antibodies Papillomavirus infections Papillomavirus Infections - diagnosis Paraffin Proteins Rabbits Rafts Sequence Homology, Amino Acid Sexually transmitted diseases Studies Uterine Cervical Neoplasms - pathology Uterine Cervical Neoplasms - virology Viral infections Western blotting Womens health |
| title | E4 antibodies facilitate detection and type-assignment of active HPV infection in cervical disease |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T05%3A03%3A29IST&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=E4%20antibodies%20facilitate%20detection%20and%20type-assignment%20of%20active%20HPV%20infection%20in%20cervical%20disease&rft.jtitle=PloS%20one&rft.au=Griffin,%20Heather&rft.date=2012-12-03&rft.volume=7&rft.issue=12&rft.spage=e49974&rft.epage=e49974&rft.pages=e49974-e49974&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0049974&rft_dat=%3Cgale_plos_%3EA477090446%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=1326751735&rft_id=info:pmid/23226504&rft_galeid=A477090446&rft_doaj_id=oai_doaj_org_article_1e1623690b7943f384e7754dffd52773&rfr_iscdi=true |