{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T23:32:17Z","timestamp":1784331137096,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013772","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000}}],"reference-count":88,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U01 CA295050"],"award-info":[{"award-number":["U01 CA295050"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01 CA239593"],"award-info":[{"award-number":["R01 CA239593"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30 CA015704"],"award-info":[{"award-number":["P30 CA015704"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic virus that causes Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease. A vaccine that prevents KSHV infection or serves in the treatment of KSHV-related diseases represents a critical unmet need, however, the types of immune responses a vaccine should elicit have not been well defined. The gH\/gL glycoprotein complex is an important target of KSHV-neutralizing antibodies, but the epitope specificities targeted by these antibodies remain unknown. Here, we isolated 12 gH\/gL-specific monoclonal antibodies (mAbs) from KSHV-infected donors and performed structure\/function analyses. These mAbs bind recombinant gH\/gL with nanomolar affinities and epitope binning analyses revealed that the mAbs bind to 5 epitope clusters on gH\/gL. Seven mAbs were able to neutralize KSHV infection of epithelial cell lines. Two potent neutralizing mAbs mapped to the EphA2 binding site as determined by inhibition of the receptor-ligand interaction and negative stain electron microscopy (nsEM) of the mAb\/gH\/gL complex. The epitopes of other neutralizing mAbs targeting novel sites of vulnerability were determined by a combination of cryogenic electron microscopy and nsEM. Together, these mAbs help to define the relevant epitope targets for KSHV vaccine design, have utility in understanding the role of antibodies in preventing KSHV infection, enable the development of immunotherapy approaches, and provide valuable tools to understand the molecular details of the KSHV entry process.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013772","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T21:01:09Z","timestamp":1767819669000},"page":"e1013772","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Monoclonal neutralizing antibodies elicited by infection with Kaposi sarcoma-associated herpesvirus reveal critical sites of vulnerability on gH\/gL"],"prefix":"10.1371","volume":"22","author":[{"given":"Yu-Hsin","family":"Wan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Pernikoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas T.","family":"Aldridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly M.","family":"Dudley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel C.","family":"Scharffenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gargi","family":"Kher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren","family":"Phipps","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Pancera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Boonyaratanakornkit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1841-6859","authenticated-orcid":true,"given":"Andrew T.","family":"McGuire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"issue":"5192","key":"ppat.1013772.ref001","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1126\/science.7997879","article-title":"Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi\u2019s sarcoma","volume":"266","author":"Y Chang","year":"1994","journal-title":"Science"},{"issue":"4","key":"ppat.1013772.ref002","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1182\/blood.V86.4.1276.bloodjournal8641276","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman\u2019s disease","volume":"86","author":"J Soulier","year":"1995","journal-title":"Blood"},{"issue":"18","key":"ppat.1013772.ref003","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1056\/NEJM199505043321802","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas","volume":"332","author":"E Cesarman","year":"1995","journal-title":"N Engl J Med"},{"issue":"3","key":"ppat.1013772.ref004","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1086\/654798","article-title":"An interleukin-6-related systemic inflammatory syndrome in patients co-infected with Kaposi sarcoma-associated herpesvirus and HIV but without Multicentric Castleman disease","volume":"51","year":"2010","journal-title":"Clin Infect Dis"},{"issue":"19","key":"ppat.1013772.ref005","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1056\/NEJM200011093431904","article-title":"Mucosal shedding of human herpesvirus 8 in men","volume":"343","author":"J Pauk","year":"2000","journal-title":"N Engl J Med"},{"issue":"3","key":"ppat.1013772.ref006","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1086\/600103","article-title":"Kaposi sarcoma-associated herpesvirus (KSHV) seroprevalence in population-based samples of African children: evidence for at least 2 patterns of KSHV transmission","volume":"200","author":"LM Butler","year":"2009","journal-title":"J Infect Dis"},{"issue":"2","key":"ppat.1013772.ref007","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1158\/1055-9965.EPI-13-0730","article-title":"Risk factors for early childhood infection of human herpesvirus-8 in Zambian children: the role of early childhood feeding practices","volume":"23","author":"KL Crabtree","year":"2014","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"issue":"12","key":"ppat.1013772.ref008","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1093\/infdis\/jis278","article-title":"Transmission of human herpesvirus type 8 infection within families in american indigenous populations from the Brazilian Amazon","volume":"205","author":"JD Borges","year":"2012","journal-title":"J Infect 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Roshan","year":"2017","journal-title":"Oncotarget"},{"issue":"6","key":"ppat.1013772.ref018","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0005890","article-title":"The CD8 and CD4 T-cell response against Kaposi\u2019s sarcoma-associated herpesvirus is skewed towards early and late lytic antigens","volume":"4","author":"RC Robey","year":"2009","journal-title":"PLoS One"},{"issue":"7","key":"ppat.1013772.ref019","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1128\/CVI.00131-10","article-title":"Correlates of protection induced by vaccination","volume":"17","author":"SA Plotkin","year":"2010","journal-title":"Clin Vaccine Immunol"},{"issue":"9","key":"ppat.1013772.ref020","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1016\/j.vaccine.2019.10.046","article-title":"Updates on immunologic correlates of vaccine-induced protection","volume":"38","author":"SA 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Akula","year":"2001","journal-title":"Virology"},{"issue":"10","key":"ppat.1013772.ref030","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus glycoprotein K8.1 is critical for infection in a cell-specific manner and functions at the attachment step on keratinocytes","volume":"97","author":"S Liu","year":"2023","journal-title":"J Virol"},{"issue":"6","key":"ppat.1013772.ref031","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01876-18","article-title":"Glycoprotein K8.1A of Kaposi\u2019s Sarcoma-Associated Herpesvirus Is a Critical B Cell Tropism Determinant Independent of Its Heparan Sulfate Binding Activity","volume":"93","author":"SJ Dollery","year":"2019","journal-title":"J Virol"},{"issue":"12","key":"ppat.1013772.ref032","doi-asserted-by":"crossref","first-page":"6389","DOI":"10.1128\/JVI.78.12.6389-6398.2004","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus glycoprotein K8.1 is dispensable for virus entry","volume":"78","author":"RE Luna","year":"2004","journal-title":"J Virol"},{"issue":"6","key":"ppat.1013772.ref033","doi-asserted-by":"crossref","DOI":"10.1128\/jvi.00576-24","article-title":"Kaposi sarcoma-associated herpesvirus complement control protein (KCP) and glycoprotein K8.1 are not required for viral infection in vitro or in vivo","volume":"98","author":"M Muniraju","year":"2024","journal-title":"J Virol"},{"issue":"2","key":"ppat.1013772.ref034","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/s41579-020-00448-w","article-title":"The structural basis of herpesvirus entry","volume":"19","author":"SA Connolly","year":"2021","journal-title":"Nat Rev Microbiol"},{"issue":"2","key":"ppat.1013772.ref035","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1006\/viro.2001.0921","article-title":"Human herpesvirus 8 envelope-associated glycoprotein B interacts with heparan sulfate-like moieties","volume":"284","author":"SM Akula","year":"2001","journal-title":"Virology"},{"issue":"1","key":"ppat.1013772.ref036","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.virol.2010.07.012","article-title":"Characterization of entry and infection of monocytic THP-1 cells by Kaposi\u2019s sarcoma associated herpesvirus (KSHV): role of heparan sulfate, DC-SIGN, integrins and signaling","volume":"406","author":"N Kerur","year":"2010","journal-title":"Virology"},{"issue":"3","key":"ppat.1013772.ref037","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S0092-8674(02)00628-1","article-title":"Integrin alpha3beta1 (CD 49c\/29) is a cellular receptor for Kaposi\u2019s sarcoma-associated herpesvirus (KSHV\/HHV-8) entry into the target cells","volume":"108","author":"SM Akula","year":"2002","journal-title":"Cell"},{"issue":"3","key":"ppat.1013772.ref038","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1128\/JVI.01673-07","article-title":"Integrin alphaVbeta3 Binds to the RGD motif of glycoprotein B of Kaposi\u2019s sarcoma-associated herpesvirus and functions as an RGD-dependent entry receptor","volume":"82","author":"HJ Garrigues","year":"2008","journal-title":"J Virol"},{"issue":"24","key":"ppat.1013772.ref039","doi-asserted-by":"crossref","first-page":"12126","DOI":"10.1128\/JVI.01146-08","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus forms a multimolecular complex of integrins (alphaVbeta5, alphaVbeta3, and alpha3beta1) and CD98-xCT during infection of human dermal microvascular endothelial cells, and CD98-xCT is essential for the postentry stage of infection","volume":"82","author":"MV Veettil","year":"2008","journal-title":"J Virol"},{"issue":"17","key":"ppat.1013772.ref040","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00803-18","article-title":"A Kaposi\u2019s sarcoma-associated herpesvirus infection mechanism is independent of integrins \u03b13\u03b21, \u03b1V\u03b23, and \u03b1V\u03b25","volume":"92","author":"AA 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Light","year":"2021","journal-title":"PLoS Biol"},{"issue":"16","key":"ppat.1013772.ref047","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00630-19","article-title":"Kaposi Sarcoma-Associated Herpesvirus Glycoprotein H Is Indispensable for Infection of Epithelial, Endothelial, and Fibroblast Cell Types","volume":"93","author":"M Muniraju","year":"2019","journal-title":"J Virol"},{"issue":"2","key":"ppat.1013772.ref048","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/jmv.20167","article-title":"Comparison of serologic responses between Kaposi\u2019s sarcoma-positive and -negative men who were seropositive for both human herpesvirus 8 and human immunodeficiency virus","volume":"74","author":"N Inoue","year":"2004","journal-title":"J Med Virol"},{"issue":"3","key":"ppat.1013772.ref049","doi-asserted-by":"crossref","first-page":"256","DOI":"10.3390\/v12030256","article-title":"The Kaposi\u2019s Sarcoma-Associated Herpesvirus (KSHV) gH\/gL Complex Is the Predominant Neutralizing Antigenic Determinant in KSHV-Infected Individuals","volume":"12","author":"Y Mortazavi","year":"2020","journal-title":"Viruses"},{"issue":"1","key":"ppat.1013772.ref050","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1128\/JVI.01170-08","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus gH\/gL: glycoprotein export and interaction with cellular receptors","volume":"83","author":"A Hahn","year":"2009","journal-title":"J Virol"},{"issue":"1","key":"ppat.1013772.ref051","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1097\/QAD.0000000000003376","article-title":"A prospective study of clinical outcomes of HIV-associated and HIV-negative Kaposi sarcoma in Uganda","volume":"37","author":"W Phipps","year":"2023","journal-title":"AIDS"},{"key":"ppat.1013772.ref052","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.jim.2007.09.017","article-title":"Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning","volume":"329","author":"T Tiller","year":"2008","journal-title":"J Immunol Methods"},{"issue":"2","key":"ppat.1013772.ref053","doi-asserted-by":"crossref","first-page":"109353","DOI":"10.1016\/j.celrep.2021.109353","article-title":"Isolation and characterization of cross-neutralizing coronavirus antibodies from COVID-19+ subjects","volume":"36","author":"MF Jennewein","year":"2021","journal-title":"Cell Rep"},{"issue":"18","key":"ppat.1013772.ref054","doi-asserted-by":"crossref","first-page":"9708","DOI":"10.1128\/JVI.01019-12","article-title":"Construction and manipulation of a new Kaposi\u2019s sarcoma-associated herpesvirus bacterial artificial chromosome clone","volume":"86","author":"KF Brulois","year":"2012","journal-title":"J Virol"},{"issue":"1","key":"ppat.1013772.ref055","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus (KSHV) gB dictates a low-pH endocytotic entry pathway as revealed by a dual-fluorescent virus system and a rhesus monkey rhadinovirus expressing KSHV gB","volume":"21","author":"S Liu","year":"2025","journal-title":"PLoS Pathog"},{"key":"ppat.1013772.ref056","article-title":"Identifying candidates for the entry receptor for Kaposi\u2019s sarcoma-associated herpesvirus in B-cells","author":"B Brumbaugh","year":"2024","journal-title":"Abstracts from The International Symposium on EBV & KSHV & Related Agents & Diseases, Boston, MA, United States"},{"issue":"4","key":"ppat.1013772.ref057","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.immuni.2018.03.026","article-title":"An antibody targeting the fusion machinery neutralizes dual-tropic infection and defines a site of vulnerability on Epstein-Barr virus","volume":"48","author":"J Snijder","year":"2018","journal-title":"Immunity"},{"issue":"3","key":"ppat.1013772.ref058","doi-asserted-by":"crossref","first-page":"541","DOI":"10.3390\/v14030541","article-title":"Antibodies targeting KSHV gH\/gL reveal distinct neutralization 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