Universität zu Köln

Hoesel, Marianna, Lucifora, Julie, Michler, Thomas ORCID: 0000-0002-4174-3316, Holz, Gisela, Gruffaz, Marion, Stahnke, Stephanie, Zoulim, Fabien ORCID: 0000-0002-2245-0083, Durantel, David ORCID: 0000-0002-9226-3419, Heikenwalder, Mathias, Nierhoff, Dirk, Millet, Rachel, Salvetti, Anna ORCID: 0000-0003-2007-8350, Protzer, Ulrike ORCID: 0000-0002-9421-1911 and Buening, Hildegard (2014). Hepatitis B Virus Infection Enhances Susceptibility Toward Adeno-Associated Viral Vector Transduction In Vitro and In Vivo. Hepatology, 59 (6). S. 2110 - 2121. HOBOKEN: WILEY-BLACKWELL. ISSN 1527-3350

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Abstract

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 in vivo 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 in vivo 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 in vivo using HBV transgenic mice and could successfully be applied to inhibit HBV progeny release. Conclusion: 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hoesel, Marianna UNSPECIFIED UNSPECIFIED UNSPECIFIED Lucifora, Julie UNSPECIFIED UNSPECIFIED UNSPECIFIED Michler, Thomas UNSPECIFIED orcid.org/0000-0002-4174-3316 UNSPECIFIED Holz, Gisela UNSPECIFIED UNSPECIFIED UNSPECIFIED Gruffaz, Marion UNSPECIFIED UNSPECIFIED UNSPECIFIED Stahnke, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Zoulim, Fabien UNSPECIFIED orcid.org/0000-0002-2245-0083 UNSPECIFIED Durantel, David UNSPECIFIED orcid.org/0000-0002-9226-3419 UNSPECIFIED Heikenwalder, Mathias UNSPECIFIED UNSPECIFIED UNSPECIFIED Nierhoff, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Millet, Rachel UNSPECIFIED UNSPECIFIED UNSPECIFIED Salvetti, Anna UNSPECIFIED orcid.org/0000-0003-2007-8350 UNSPECIFIED Protzer, Ulrike UNSPECIFIED orcid.org/0000-0002-9421-1911 UNSPECIFIED Buening, Hildegard UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-437470
DOI:	10.1002/hep.26990
Journal or Publication Title:	Hepatology
Volume:	59
Number:	6
Page Range:	S. 2110 - 2121
Date:	2014
Publisher:	WILEY-BLACKWELL
Place of Publication:	HOBOKEN
ISSN:	1527-3350
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENE-TRANSFER; X PROTEIN; IMMUNE-RESPONSE; REPLICATION; TYPE-2; ENDOCYTOSIS; ACTIVATION; INTEGRIN; MOUSE; LIVER Multiple languages Gastroenterology & Hepatology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43747