Rapid uncoating of vector genomes is the key to efficient liver transduction with pseudotyped adeno-associated virus vectors.

Abstract:

:Transduction of the liver with single-stranded adeno-associated virus serotype 2 (AAV2) vectors is inefficient; less than 10% of hepatocytes are permissive for stable transduction, and transgene expression is characterized by a lag phase of up to 6 weeks. AAV2-based vector genomes packaged inside AAV6 or AAV8 capsids can transduce the liver with higher efficiency, but the molecular mechanisms underlying this phenomenon have not been determined. We now show that the primary barrier to transduction of the liver with vectors based on AAV2 capsids is uncoating of vector genomes in the nucleus. The majority of AAV2 genomes persist as encapsidated single-stranded molecules within the nucleus for as long as 6 weeks after vector administration. Double-stranded vector genomes packaged inside AAV2 capsids are at least 50-fold more active than single-stranded counterparts, but these vectors also exhibit a lag phase before maximal gene expression. Vector genomes packaged inside AAV6 or AAV8 capsids do not persist as encapsidated molecules and are more biologically active than vector genomes packaged inside AAV2 capsids. Our data suggest that the rate of uncoating of vector genomes determines the ability of complementary plus and minus single-stranded genomes to anneal together and convert to stable, biologically active double-stranded molecular forms.

journal_name

J Virol

journal_title

Journal of virology

authors

Thomas CE,Storm TA,Huang Z,Kay MA

doi

10.1128/jvi.78.6.3110-3122.2004

subject

Has Abstract

pub_date

2004-03-01 00:00:00

pages

3110-22

issue

6

eissn

0022-538X

issn

1098-5514

journal_volume

78

pub_type

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