{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:28:27Z","timestamp":1791300507949,"version":"4.1.0"},"reference-count":36,"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":457,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Gene therapy has become an accepted concept for the treatment of a variety of different diseases. In contrast to preclinical models, subjects enrolled in clinical trials, including gene therapy, possess a history of infection with microbes that may influence its safety and efficacy. Especially, viruses that establish chronic infections in the liver, one of the main targets for <jats:italic toggle=\"yes\">in vivo<\/jats:italic> gene therapy, raise important concerns. Among them is the hepatitis B virus (HBV), which has chronically infected more than 350 million people worldwide. Here, we investigated the effect of HBV on adeno-associated viral (AAV) vectors, the most frequently applied gene transfer vehicles for <jats:italic toggle=\"yes\">in vivo<\/jats:italic> gene therapy. Unexpectedly, we found that HBV greatly improved AAV transduction in cells replicating HBV and identified HBV protein x (HBx) as a key factor. Whereas HBV-positive and -negative cells were indistinguishable with respect to cell-entry efficiency, significantly higher numbers of AAV vector genomes were successfully delivered to the nucleus in the presence of HBV. The HBV-promoting effect was abolished by inhibitors of phosphatidylinositol 3-kinase (PI3K). PI3K was required for efficient trafficking of AAV to the nucleus and was enhanced in HBV-replicating cells and upon HBx expression. Enhancement of AAV transduction was confirmed <jats:italic toggle=\"yes\">in vivo<\/jats:italic> using HBV transgenic mice and could successfully be applied to inhibit HBV progeny release. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Our results demonstrate that acute, as well as chronic, infections with unrelated viruses change the intracellular milieu, thereby likely influencing gene therapy outcomes. In the case of HBV, HBx-mediated enhancement of AAV transduction is an advantage that could be exploited for development of novel treatments of HBV infection. (Hepatology 2014;59:2110-2120)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.26990","type":"journal-article","created":{"date-parts":[[2014,1,15]],"date-time":"2014-01-15T01:41:44Z","timestamp":1389750104000},"page":"2110-2120","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":24,"title":["Hepatitis B virus infection enhances susceptibility toward adeno-associated viral vector transduction in vitro and in vivo"],"prefix":"10.1097","volume":"59","author":[{"given":"Marianna","family":"H\u00f6sel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Lucifora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Michler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisela","family":"Holz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Gruffaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Stahnke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabien","family":"Zoulim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Durantel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Heikenwalder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Nierhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Millet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Salvetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Protzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hildegard","family":"B\u00fcning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-12-20251014","first-page":"341355","article-title":"Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges.","volume":"12","author":"Mingozzi","year":"2011","journal-title":"Nat Rev Genet"},{"key":"R2-12-20251014","doi-asserted-by":"crossref","first-page":"14381445","DOI":"10.1128\/JVI.72.2.1438-1445.1998","article-title":"Membraneassociated heparan sulfate proteoglycan is a receptor for adenoassociated virus type 2 virions.","volume":"72","author":"Summerford","year":"1998","journal-title":"J Virol"},{"key":"R3-12-20251014","doi-asserted-by":"crossref","first-page":"89618969","DOI":"10.1128\/JVI.00843-06","article-title":"Adenoassociated virus type 2 contains an integrin alpha5beta1 binding domain essential for viral cell entry.","volume":"80","author":"Asokan","year":"2006","journal-title":"J Virol"},{"key":"R4-12-20251014","doi-asserted-by":"crossref","first-page":"7882","DOI":"10.1038\/4768","article-title":"AlphaVbeta5 integrin: a coreceptor for adenoassociated virus type 2 infection.","volume":"5","author":"Summerford","year":"1999","journal-title":"Nat Med"},{"key":"R5-12-20251014","doi-asserted-by":"crossref","first-page":"972983","DOI":"10.1038\/mt.2011.295","article-title":"Directing integrinlinked endocytosis of recombinant AAV enhances productive FAKdependent transduction.","volume":"20","author":"Kaminsky","year":"2012","journal-title":"Mol Ther"},{"key":"R6-12-20251014","doi-asserted-by":"crossref","first-page":"91849196","DOI":"10.1128\/JVI.74.19.9184-9196.2000","article-title":"Endocytosis and nuclear trafficking of adenoassociated virus type 2 are controlled by rac1 and phosphatidylinositol3 kinase activation.","volume":"74","author":"Sanlioglu","year":"2000","journal-title":"J Virol"},{"key":"R7-12-20251014","doi-asserted-by":"crossref","first-page":"44824487","DOI":"10.1182\/blood-2012-05-423210","article-title":"The gene therapy journey for hemophilia: are we there yet?","volume":"120","author":"High","year":"2012","journal-title":"Blood"},{"key":"R8-12-20251014","doi-asserted-by":"crossref","first-page":"27312738","DOI":"10.4049\/jimmunol.172.5.2731","article-title":"Of mice and not men: differences between mouse and human immunology.","volume":"172","author":"Mestas","year":"2004","journal-title":"J Immunol"},{"key":"R9-12-20251014","doi-asserted-by":"crossref","first-page":"29462951","DOI":"10.1073\/pnas.1222738110","article-title":"Conservation and divergence in the transcriptional programs of the human and mouse immune systems.","volume":"110","author":"Shay","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R10-12-20251014","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1182\/blood-2013-01-306647","article-title":"Immune responses to AAV vectors: overcoming barriers to successful gene therapy.","volume":"122","author":"Mingozzi","year":"2013","journal-title":"Blood"},{"key":"R12-12-20251014","doi-asserted-by":"crossref","first-page":"1491314918","DOI":"10.1073\/pnas.0406282101","article-title":"A function of the hepatitis B virus precore protein is to regulate the immune response to the core antigen.","volume":"101","author":"Chen","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R13-12-20251014","doi-asserted-by":"crossref","first-page":"9961003","DOI":"10.1016\/j.jhep.2011.02.015","article-title":"Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection.","volume":"55","author":"Lucifora","year":"2011","journal-title":"J Hepatol"},{"key":"R14-12-20251014","doi-asserted-by":"crossref","first-page":"287297","DOI":"10.1002\/hep.24625","article-title":"Tolllike receptor 2mediated innate immune response in human nonparenchymal liver cells toward adenoassociated viral vectors.","volume":"55","author":"Hosel","year":"2012","journal-title":"Hepatology"},{"key":"R15-12-20251014","doi-asserted-by":"crossref","first-page":"22242232","DOI":"10.1128\/JVI.72.3.2224-2232.1998","article-title":"Production of hightiter recombinant adenoassociated virus vectors in the absence of helper adenovirus.","volume":"72","author":"Xiao","year":"1998","journal-title":"J Virol"},{"key":"R16-12-20251014","doi-asserted-by":"crossref","first-page":"14291438","DOI":"10.1002\/jgm.782","article-title":"Adenoassociated virus serotypes 1 to 5 mediated tumor cell directed gene transfer and improvement of transduction efficiency.","volume":"7","author":"Hacker","year":"2005","journal-title":"J Gene Med"},{"key":"RU17-12-20251014","doi-asserted-by":"crossref","first-page":"63816388","DOI":"10.1128\/JVI.78.12.6381-6388.2004","article-title":"Clades of adenoassociated viruses are widely disseminated in human tissues.","volume":"78","author":"Gao","year":"2004","journal-title":"J Virol"},{"key":"R18-12-20251014","doi-asserted-by":"crossref","first-page":"210218","DOI":"10.1038\/gt.2011.78","article-title":"Successful target cell transduction of capsidengineered rAAV vectors requires clathrindependent endocytosis.","volume":"19","author":"Uhrig","year":"2012","journal-title":"Gene Ther"},{"key":"R19-12-20251014","doi-asserted-by":"crossref","first-page":"4956","DOI":"10.1023\/A:1026392429112","article-title":"Charitable statecontrolled foundation human tissue and cell research: ethic and legal aspects in the supply of surgically removed human tissue for research in the academic and commercial sector in Germany.","volume":"4","author":"Thasler","year":"2003","journal-title":"Cell Tissue Bank"},{"key":"R20-12-20251014","first-page":"736744","article-title":"Primary human hepatocytesa valuable tool for investigation of apoptosis and hepatitis B virus infection.","volume":"38","author":"SchulzeBergkamen","year":"2003","journal-title":"J Hepatol"},{"key":"RU21-12-20251014","doi-asserted-by":"crossref","first-page":"203210","DOI":"10.1089\/104303404772680001","article-title":"Hepatitis B virusbased vectors allow the elimination of viral gene expression and the insertion of foreign promoters.","volume":"15","author":"Untergasser","year":"2004","journal-title":"Hum Gene Ther"},{"key":"R22-12-20251014","doi-asserted-by":"crossref","first-page":"1565515660","DOI":"10.1073\/pnas.232137699","article-title":"Infection of a human hepatoma cell line by hepatitis B virus.","volume":"99","author":"Gripon","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R23-12-20251014","doi-asserted-by":"crossref","first-page":"668677","DOI":"10.1038\/sj.gt.3302449","article-title":"Liverspecific expression of interferon gamma following adenoviral gene transfer controls hepatitis B virus replication in mice.","volume":"12","author":"Dumortier","year":"2005","journal-title":"Gene Ther"},{"key":"R24-12-20251014","doi-asserted-by":"crossref","first-page":"31063119","DOI":"10.1172\/JCI43565","article-title":"Argonaute proteins are key determinants of RNAi efficacy, toxicity, and persistence in the adult mouse liver.","volume":"120","author":"Grimm","year":"2010","journal-title":"J Clin Invest"},{"key":"R25-12-20251014","doi-asserted-by":"crossref","first-page":"675684","DOI":"10.1002\/hep.21282","article-title":"Peginterferon alpha2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B.","volume":"44","author":"Wursthorn","year":"2006","journal-title":"Hepatology"},{"key":"R26-12-20251014","doi-asserted-by":"crossref","first-page":"44064414","DOI":"10.1128\/JVI.80.9.4406-4414.2006","article-title":"Activation of focal adhesion kinase by hepatitis B virus HBx protein: multiple functions in viral replication.","volume":"80","author":"Bouchard","year":"2006","journal-title":"J Virol"},{"key":"R27-12-20251014","doi-asserted-by":"crossref","first-page":"1696916977","DOI":"10.1074\/jbc.M011263200","article-title":"The hepatitis B virusX protein activates a phosphatidylinositol 3kinasedependent survival signaling cascade.","volume":"276","author":"Lee","year":"2001","journal-title":"J Biol Chem"},{"key":"R28-12-20251014","doi-asserted-by":"crossref","first-page":"93329340","DOI":"10.1128\/JVI.00918-10","article-title":"Interferons accelerate decay of replicationcompetent nucleocapsids of hepatitis B virus.","volume":"84","author":"Xu","year":"2010","journal-title":"J Virol"},{"key":"R29-12-20251014","doi-asserted-by":"crossref","first-page":"717733","DOI":"10.1002\/jgm.1205","article-title":"Recent developments in adenoassociated virus vector technology.","volume":"10","author":"Buning","year":"2008","journal-title":"J Gene Med"},{"key":"R30-12-20251014","doi-asserted-by":"crossref","first-page":"82828287","DOI":"10.1128\/jvi.68.12.8282-8287.1994","article-title":"DNAdamaging agents greatly increase the transduction of nondividing cells by adenoassociated virus vectors.","volume":"68","author":"Alexander","year":"1994","journal-title":"J Virol"},{"key":"R31-12-20251014","doi-asserted-by":"crossref","first-page":"57195723","DOI":"10.1073\/pnas.92.12.5719","article-title":"DNA synthesis and topoisomerase inhibitors increase transduction by adenoassociated virus vectors.","volume":"92","author":"Russell","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R32-12-20251014","doi-asserted-by":"crossref","first-page":"e59142","DOI":"10.1371\/journal.pone.0059142","article-title":"Optimization of the capsid of recombinant adenoassociated virus 2 (AAV2) vectors: the final threshold?","volume":"8","author":"Aslanidi","year":"2013","journal-title":"PLoS One"},{"key":"R33-12-20251014","doi-asserted-by":"crossref","first-page":"18241833","DOI":"10.1128\/JVI.75.4.1824-1833.2001","article-title":"Intracellular trafficking of adenoassociated virus vectors: routing to the late endosomal compartment and proteasome degradation.","volume":"75","author":"Douar","year":"2001","journal-title":"J Virol"},{"key":"R34-12-20251014","doi-asserted-by":"crossref","first-page":"12871293","DOI":"10.1038\/gt.2008.89","article-title":"Strategies for improving the transduction efficiency of singlestranded adenoassociated virus vectors in vitro and in vivo.","volume":"15","author":"Jayandharan","year":"2008","journal-title":"Gene Ther"},{"key":"R35-12-20251014","doi-asserted-by":"crossref","first-page":"4252","DOI":"10.1002\/hep.21467","article-title":"Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.","volume":"45","author":"Boyault","year":"2007","journal-title":"Hepatology"},{"key":"R36-12-20251014","doi-asserted-by":"crossref","first-page":"1007210080","DOI":"10.1128\/JVI.00541-07","article-title":"Regulation of hepatitis B virus replication by the phosphatidylinositol 3kinaseakt signal transduction pathway.","volume":"81","author":"Guo","year":"2007","journal-title":"J Virol"},{"key":"R37-12-20251014","doi-asserted-by":"crossref","first-page":"2585825864","DOI":"10.1074\/jbc.M003578200","article-title":"Hepatitis B virus X protein inhibits transforming growth factorbetainduced apoptosis through the activation of phosphatidylinositol 3kinase pathway.","volume":"275","author":"Shih","year":"2000","journal-title":"J Biol Chem"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.26990","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201406000-00012","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T15:54:23Z","timestamp":1760457263000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201406000-00012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6]]},"references-count":36,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2014]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.26990","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2014,6]]}}}