Integration of retroviral cDNA into a host cell chromosome is a central feature of viral replication, but the determinants of integration target site selection remain uncertain. We have taken advantage of the draft human genome sequence to map sites of HIV cDNA integration and assess the relationship between integration acceptor sites and chromosomal features. Mapping of 524 independent sites of HIV cDNA integration in SupT1 cells revealed that 69% of integration sites were in transcription units, indicating that active genes are favored as targets. Transcriptional profiling of the target cells revealed that transcriptional activity correlated with targeting of genes for integration. Integration hotspots were also detected, including a 2 kb chromosomal region containing 5 independent integrated proviruses, 1% of the integration events analyzed. These data reveal that HIV integration is highly biased in the human genome, providing new perspective on HIV integration mechanism. These data are also important for assessing the safety of retroviral vectors in gene therapy, and the use of retroviruses as insertional mutagenesis. To extend this study, the following specific aims will be addressed: To characterize integration site selection in primary human cells; To characterize integration site selection by MLV; To investigate the mechanisms directing integration targeting; and to characterize integration sites in patient samples.
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