Integration preferences of wildtype AAV-2 for consensus rep-binding sites at numerous loci in the human genome.

PLoS Pathogens
Daniela HüserRegine Heilbronn

Abstract

Adeno-associated virus type 2 (AAV) is known to establish latency by preferential integration in human chromosome 19q13.42. The AAV non-structural protein Rep appears to target a site called AAVS1 by simultaneously binding to Rep-binding sites (RBS) present on the AAV genome and within AAVS1. In the absence of Rep, as is the case with AAV vectors, chromosomal integration is rare and random. For a genome-wide survey of wildtype AAV integration a linker-selection-mediated (LSM)-PCR strategy was designed to retrieve AAV-chromosomal junctions. DNA sequence determination revealed wildtype AAV integration sites scattered over the entire human genome. The bioinformatic analysis of these integration sites compared to those of rep-deficient AAV vectors revealed a highly significant overrepresentation of integration events near to consensus RBS. Integration hotspots included AAVS1 with 10% of total events. Novel hotspots near consensus RBS were identified on chromosome 5p13.3 denoted AAVS2 and on chromsome 3p24.3 denoted AAVS3. AAVS2 displayed seven independent junctions clustered within only 14 bp of a consensus RBS which proved to bind Rep in vitro similar to the RBS in AAVS3. Expression of Rep in the presence of rep-deficient AAV vect...Continue Reading

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Datasets Mentioned

BETA
AF043303

Methods Mentioned

BETA
PCR
transfections
transfection
Electrophoretic mobility shift
immunoprecipitation
nucleotide exchange
electrophoresis
ChIP-Seq

Software Mentioned

Bowtie
MACS
BLAT
SeqAn

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