{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:42:50Z","timestamp":1792701770349,"version":"4.5.0"},"reference-count":50,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2016,1,1]],"date-time":"2016-01-01T00:00:00Z","timestamp":1451606400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Adeno-associated virus 2 (AAV2) and adenovirus 5 (Ad5) are promising gene therapy vectors. Both display liver tropism and are currently thought to enter hepatocytes\n            <jats:italic>in vivo<\/jats:italic>\n            through cell surface heparan sulfate proteoglycans (HSPGs). To test directly this hypothesis, we created mice that lack\n            <jats:italic>Ext1<\/jats:italic>\n            , an enzyme required for heparan sulfate biosynthesis, in hepatocytes.\n            <jats:italic>Ext1<\/jats:italic>\n            <jats:sup>\n              <jats:italic>HEP<\/jats:italic>\n            <\/jats:sup>\n            mutant mice exhibit an 8-fold reduction of heparan sulfate in primary hepatocytes and a 5-fold reduction of heparan sulfate in whole liver tissue. Conditional hepatocyte\n            <jats:italic>Ext1<\/jats:italic>\n            gene deletion greatly reduced AAV2 liver transduction following intravenous injection. Ad5 transduction requires blood coagulation factor X (FX); FX binds to the Ad5 capsid hexon protein and bridges the virus to HSPGs on the cell surface. Ad5.FX transduction was abrogated in primary hepatocytes from\n            <jats:italic>Ext1<\/jats:italic>\n            <jats:sup>\n              <jats:italic>HEP<\/jats:italic>\n            <\/jats:sup>\n            mice. However, in contrast to the case with AAV2, Ad5 transduction was not significantly reduced in the livers of\n            <jats:italic>Ext1<\/jats:italic>\n            <jats:sup>\n              <jats:italic>HEP<\/jats:italic>\n            <\/jats:sup>\n            mice. FX remained essential for Ad5 transduction\n            <jats:italic>in vivo<\/jats:italic>\n            in\n            <jats:italic>Ext1<\/jats:italic>\n            <jats:sup>\n              <jats:italic>HEP<\/jats:italic>\n            <\/jats:sup>\n            mice. We conclude that while AAV2 requires HSPGs for entry into mouse hepatocytes, HSPGs are dispensable for Ad5 hepatocyte transduction\n            <jats:italic>in vivo<\/jats:italic>\n            . This study reopens the question of how adenovirus enters cells\n            <jats:italic>in vivo<\/jats:italic>\n            .\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Our understanding of how viruses enter cells, and how they can be used as therapeutic vectors to manage disease, begins with identification of the cell surface receptors to which viruses bind and which mediate viral entry. Both adeno-associated virus 2 and adenovirus 5 are currently thought to enter hepatocytes\n            <jats:italic>in vivo<\/jats:italic>\n            through heparan sulfate proteoglycans (HSPGs). However, direct evidence for these conclusions is lacking. Experiments presented herein, in which hepatic heparan sulfate synthesis was genetically abolished, demonstrated that HSPGs are not likely to function as hepatocyte Ad5 receptors\n            <jats:italic>in vivo<\/jats:italic>\n            . The data also demonstrate that HSPGs are required for hepatocyte transduction by AAV2. These results reopen the question of the identity of the Ad5 receptor\n            <jats:italic>in vivo<\/jats:italic>\n            and emphasize the necessity of demonstrating the nature of the receptor by genetic means, both for understanding Ad5 entry into cells\n            <jats:italic>in vivo<\/jats:italic>\n            and for optimization of Ad5 vectors as therapeutic agents.\n          <\/jats:p>","DOI":"10.1128\/jvi.01939-15","type":"journal-article","created":{"date-parts":[[2015,10,22]],"date-time":"2015-10-22T15:02:01Z","timestamp":1445526121000},"page":"412-420","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":38,"title":["Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction\n            <i>In Vivo<\/i>"],"prefix":"10.1128","volume":"90","author":[{"given":"Anne K.","family":"Zaiss","sequence":"first","affiliation":[{"name":"Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA"},{"name":"Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin M.","family":"Foley","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Lawrence","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina S.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA"},{"name":"Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamidreza","family":"Hoveida","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA"},{"name":"Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Secrest","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur 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