{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T22:36:14Z","timestamp":1778711774161,"version":"3.51.4"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:p>Extrahepatic disease manifestations are common in chronic hepatitis C virus (HCV) infection. The mechanism of HCV\u2010related lymphoproliferative disorders is not fully understood. Recent studies have found that HCV in peripheral blood mononuclear cells from chronically infected patients is mainly associated with cluster of differentiation 19\u2010positive (CD19<jats:sup>+<\/jats:sup>) B cells. To further elucidate this preferential association of HCV with B cells, we used <jats:italic toggle=\"yes\">in vitro<\/jats:italic> cultured virus and uninfected peripheral blood mononuclear cells from healthy blood donors to investigate the necessary serum components that activate the binding of HCV to B cells. First, we found that the active serum components were present not only in HCV carriers but also in HCV recovered patients and HCV\u2010negative, healthy blood donors and that the serum components were heat\u2010labile. Second, the preferential binding activity of HCV to B cells could be blocked by anti\u2010complement C3 antibodies. In experiments with complement\u2010depleted serum and purified complement proteins, we demonstrated that complement proteins C1, C2, and C3 were required to activate such binding activity. Complement protein C4 was partially involved in this process. Third, using antibodies against cell surface markers, we showed that the binding complex mainly involved CD21 (complement receptor 2), CD19, CD20, and CD81; CD35 (complement receptor 1) was involved but had lower binding activity. Fourth, both anti\u2010CD21 and anti\u2010CD35 antibodies could block the binding of patient\u2010derived HCV to B cells. Fifth, complement also mediated HCV binding to Raji cells, a cultured B\u2010cell line derived from Burkitt's lymphoma. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: In chronic HCV infection, the preferential association of HCV with B cells is mediated by the complement system, mainly through complement receptor 2 (CD21), in conjunction with the CD19 and CD81 complex. (H<jats:sc>epatology<\/jats:sc> 2016;64:1900\u20101910).<\/jats:p>","DOI":"10.1002\/hep.28842","type":"journal-article","created":{"date-parts":[[2016,9,19]],"date-time":"2016-09-19T08:53:07Z","timestamp":1474275187000},"page":"1900-1910","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":16,"title":["Preferential association of hepatitis C virus with CD19+ B cells is mediated by complement system"],"prefix":"10.1097","volume":"64","author":[{"given":"Richard Y.","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Transfusion Medicine, Clinical Center,National Institutes of Health,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Bare","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, Clinical Center,National Institutes of Health,Bethesda,MD"},{"name":"Instituto de Investigaciones Hematol\u00f3gicas,Instituto de Medicina Experimental,CONICET, Academia Nacional de Medicina,Buenos Aires,Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"De Giorgi","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, Clinical Center,National Institutes of Health,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kentaro","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, Clinical Center,National Institutes of Health,Bethesda,MD"},{"name":"Department of Gastroenterology and Metabolism,Nagoya City University Graduate School of Medical Sciences,Nagoya,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazi Abdus","family":"Salam","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, Clinical Center,National Institutes of Health,Bethesda,MD"},{"name":"Department of Biochemistry and Molecular Biology,University of Rajshahi,Rajshahi,Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Grandinetti","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, Clinical Center,National Institutes of Health,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cathy","family":"Schechterly","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, Clinical Center,National Institutes of Health,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harvey J.","family":"Alter","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, Clinical Center,National Institutes of Health,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2016,10,24]]},"reference":[{"key":"hep28842-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"2676","DOI":"10.4254\/wjh.v7.i26.2676","article-title":"Hepatitis C virus: a global view","volume":"7","year":"2015","journal-title":"World J Hepatol"},{"key":"hep28842-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/hep.21283","article-title":"Extrahepatic replication of HCV: insights into clinical manifestations and biological consequences","volume":"44","year":"2006","journal-title":"Hepatology"},{"key":"hep28842-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"327","DOI":"10.4254\/wjh.v7.i3.327","article-title":"Hepatitis C virus syndrome: a constellation of organ\u2010 and non\u2010organ specific autoimmune disorders, B\u2010cell non\u2010Hodgkin's lymphoma, and cancer","volume":"7","year":"2015","journal-title":"World J Hepatol"},{"key":"hep28842-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/ki.2009.247","article-title":"Hepatitis C virus\u2010induced cryoglobulinemia","volume":"76","year":"2009","journal-title":"Kidney Int"},{"key":"hep28842-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1177\/0961203314556140","article-title":"Extrahepatic manifestations in chronic hepatitis C virus carriers","volume":"24","year":"2015","journal-title":"Lupus"},{"key":"hep28842-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1002\/hep.22802","article-title":"Hepatitis C virus persisting after clinically apparent sustained virological response to antiviral therapy retains infectivity in vitro","volume":"49","year":"2009","journal-title":"Hepatology"},{"key":"hep28842-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1053\/j.gastro.2007.12.011","article-title":"Hepatitis C virus replicates in the same immune cell subsets in chronic hepatitis C and occult infection","volume":"134","year":"2008","journal-title":"Gastroenterology"},{"key":"hep28842-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.3748\/wjg.14.2789","article-title":"Occult persistence and lymphotropism of hepatitis C virus infection","volume":"14","year":"2008","journal-title":"World J Gastroenterol"},{"issue":"Suppl. 1","key":"hep28842-bib-0009-20241017","first-page":"S38","article-title":"Hepatitis C virus lymphotropism: lessons from a decade of studies","volume":"39","year":"2007","journal-title":"Dig Liver Dis"},{"key":"hep28842-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1002\/hep.25921","article-title":"Investigation of residual hepatitis C virus in presumed recovered subjects","volume":"57","year":"2013","journal-title":"Hepatology"},{"key":"hep28842-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1002\/hep.22706","article-title":"Occult hepatitis C: how convincing are the current data?","volume":"49","year":"2009","journal-title":"Hepatology"},{"key":"hep28842-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1086\/323391","article-title":"Quantitative analysis of hepatitis C virus in peripheral blood and liver: replication detected only in liver","volume":"184","year":"2001","journal-title":"J Infect Dis"},{"key":"hep28842-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1086\/514114","article-title":"Detection of hepatitis C virus RNA in CD19 peripheral blood mononuclear cells of chronically infected patients","volume":"176","year":"1997","journal-title":"J Infect Dis"},{"key":"hep28842-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1128\/JVI.01977-07","article-title":"The tight junction proteins claudin\u20101, \u20106, and \u20109 are entry cofactors for hepatitis C virus","volume":"82","year":"2008","journal-title":"J Virol"},{"key":"hep28842-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1002\/hep.21994","article-title":"Scavenger receptor class B type I is a key host factor for hepatitis C virus infection required for an entry step closely linked to CD81","volume":"46","year":"2007","journal-title":"Hepatology"},{"key":"hep28842-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1002\/hep.22550","article-title":"Cell culture\u2010produced hepatitis C virus does not infect peripheral blood mononuclear cells","volume":"48","year":"2008","journal-title":"Hepatology"},{"key":"hep28842-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"18544","DOI":"10.1073\/pnas.0509402102","article-title":"Activation of naive B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus\u2010associated B lymphocyte disorders","volume":"102","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"hep28842-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1182\/blood-2008-05-158824","article-title":"Hepatitis C virus association with peripheral blood B lymphocytes potentiates viral infection of liver\u2010derived hepatoma cells","volume":"113","year":"2009","journal-title":"Blood"},{"key":"hep28842-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1146\/annurev.iy.13.040195.001015","article-title":"The CD19\/CR2\/TAPA\u20101 complex of B lymphocytes: linking natural to acquired immunity","volume":"13","year":"1995","journal-title":"Annu Rev Immunol"},{"key":"hep28842-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1126\/science.1373518","article-title":"CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes","volume":"256","year":"1992","journal-title":"Science"},{"key":"hep28842-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1111\/j.0105-2896.2004.0123.x","article-title":"The lectin\u2010complement pathway\u2014its role in innate immunity and evolution","volume":"198","year":"2004","journal-title":"Immunol Rev"},{"key":"hep28842-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/ni.1923","article-title":"Complement: a key system for immune surveillance and homeostasis","volume":"11","year":"2010","journal-title":"Nat Immunol"},{"key":"hep28842-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.virol.2010.12.045","article-title":"Complement and viral pathogenesis","volume":"411","year":"2011","journal-title":"Virology"},{"key":"hep28842-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"3046","DOI":"10.1016\/j.vaccine.2007.12.003","article-title":"Complement\u2010HIV interactions during all steps of viral pathogenesis","volume":"26","year":"2008","journal-title":"Vaccine"},{"key":"hep28842-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1172\/JCI65861","article-title":"Detection of complement activation using monoclonal antibodies against C3d","volume":"123","year":"2013","journal-title":"J Clin Invest"},{"key":"hep28842-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"6409","DOI":"10.1128\/JVI.78.12.6409-6419.2004","article-title":"Direct binding of hepatitis C virus core to gC1qR on CD4+ and CD8+ T cells leads to impaired activation of Lck and Akt","volume":"78","year":"2004","journal-title":"J Virol"},{"key":"hep28842-bib-0027-20241017","first-page":"1","article-title":"The complement system: an overview","volume":"150","year":"2000","journal-title":"Methods Mol Biol"},{"key":"hep28842-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.coi.2005.03.001","article-title":"Regulation of B lymphocyte activation by complement C3 and the B cell coreceptor complex","volume":"17","year":"2005","journal-title":"Curr Opin Immunol"},{"key":"hep28842-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1084\/jem.192.5.637","article-title":"B cells of HIV\u20101\u2010infected patients bind virions through CD21\u2010complement interactions and transmit infectious virus to activated T cells","volume":"192","year":"2000","journal-title":"J Exp Med"},{"key":"hep28842-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"e1004412","DOI":"10.1371\/journal.ppat.1004412","article-title":"Exploitation of the complement system by oncogenic Kaposi's sarcoma\u2010associated herpesvirus for cell survival and persistent infection","volume":"10","year":"2014","journal-title":"PLoS Pathog"},{"key":"hep28842-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.3390\/molecules20022229","article-title":"Human lectins and their roles in viral infections","volume":"20","year":"2015","journal-title":"Molecules"},{"key":"hep28842-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/nm.2262","article-title":"Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes","volume":"17","year":"2011","journal-title":"Nat Med"},{"key":"hep28842-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"359","DOI":"10.4049\/jimmunol.0902278","article-title":"A high\u2010affinity inhibitor of human CD59 enhances complement\u2010mediated virolysis of HIV\u20101: implications for treatment of HIV\u20101\/AIDS","volume":"184","year":"2010","journal-title":"J Immunol"},{"key":"hep28842-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1007\/s13238-010-0088-9","article-title":"Specific interaction of hepatitis C virus glycoproteins with mannan binding lectin inhibits virus entry","volume":"1","year":"2010","journal-title":"Protein Cell"},{"key":"hep28842-bib-0035-20241017","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1159\/000362209","article-title":"Recombinant human L\u2010ficolin directly neutralizes hepatitis C virus entry","volume":"6","year":"2014","journal-title":"J Innate Immun"},{"key":"hep28842-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"5858","DOI":"10.1128\/JVI.00174-13","article-title":"Hepatitis C virus suppresses C9 complement synthesis and impairs membrane attack complex function","volume":"87","year":"2013","journal-title":"J Virol"},{"key":"hep28842-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1002\/hep.24686","article-title":"CD59 incorporation protects hepatitis C virus against complement\u2010mediated destruction","volume":"55","year":"2012","journal-title":"Hepatology"},{"key":"hep28842-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"7902","DOI":"10.1128\/JVI.00917-13","article-title":"Hepatitis C virus infection upregulates CD55 expression on the hepatocyte surface and promotes association with virus particles","volume":"87","year":"2013","journal-title":"J Virol"},{"key":"hep28842-bib-0039-20241017","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.jhep.2013.03.018","article-title":"Hepatitis C\u2010associated B\u2010cell non\u2010Hodgkin lymphomas. Epidemiology, molecular signature and clinical management","volume":"59","year":"2013","journal-title":"J Hepatol"},{"key":"hep28842-bib-0040-20241017","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1182\/asheducation-2014.1.590","article-title":"Hepatitis C virus\u2010associated B\u2010cell non\u2010Hodgkin lymphomas","volume":"2014","year":"2014","journal-title":"Hematology Am Soc Hematol Educ Program"},{"key":"hep28842-bib-0041-20241017","doi-asserted-by":"crossref","first-page":"4262","DOI":"10.1073\/pnas.0303971101","article-title":"Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes","volume":"101","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"hep28842-bib-0042-20241017","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1080\/1042819031000076972","article-title":"Hepatitis C virus (HCV) and lymphomagenesis","volume":"44","year":"2003","journal-title":"Leuk Lymphoma"},{"key":"hep28842-bib-0043-20241017","doi-asserted-by":"crossref","first-page":"6532","DOI":"10.4049\/jimmunol.174.10.6532","article-title":"Hepatitis C virus drives the unconstrained monoclonal expansion of VH1\u201069\u2010expressing memory B cells in type II cryoglobulinemia: a model of infection\u2010driven lymphomagenesis","volume":"174","year":"2005","journal-title":"J Immunol"},{"key":"hep28842-bib-0044-20241017","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1182\/blood.V97.4.1023","article-title":"V(H)1\u201069 gene is preferentially used by hepatitis C virus\u2010associated B cell lymphomas and by normal B cells responding to the E2 viral antigen","volume":"97","year":"2001","journal-title":"Blood"},{"key":"hep28842-bib-0045-20241017","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/S0002-9440(10)61691-4","article-title":"Immunoglobulin gene mutations and frequent use of VH1\u201069 and VH4\u201034 segments in hepatitis C virus\u2010positive and hepatitis C virus\u2010negative nodal marginal zone B\u2010cell lymphoma","volume":"159","year":"2001","journal-title":"Am J Pathol"},{"key":"hep28842-bib-0046-20241017","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1182\/blood-2013-10-532895","article-title":"B\u2010cell receptors expressed by lymphomas of hepatitis C virus (HCV)\u2010infected patients rarely react with the viral proteins","volume":"123","year":"2014","journal-title":"Blood"},{"key":"hep28842-bib-0047-20241017","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.semcancer.2013.09.001","article-title":"B\u2010cell receptor signaling as a driver of lymphoma development and evolution","volume":"23","year":"2013","journal-title":"Semin Cancer Biol"},{"key":"hep28842-bib-0048-20241017","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nri726","article-title":"Lipid rafts and B\u2010cell activation","volume":"2","year":"2002","journal-title":"Nat Rev Immunol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.28842","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.28842","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201612000-00019","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:42:22Z","timestamp":1729212142000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201612000-00019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10,24]]},"references-count":48,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2016]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.28842","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,10,24]]},"assertion":[{"value":"2016-05-24","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-08-21","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}