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Retroviral gene therapy? ASLV, HIV, and MLV show distinct target site preferences

Many diseases (including inherited disorders like cystic fibrosis to cancer) have a genetic component and gene therapy holds the promise of restoring compromised genes with their healthy counterparts. That promise was quashed when a teenager -- Jesse Gelsinger -- suffering from a rare hereditary liver disorder died after participating in an experimental gene therapy trial in 1999. In another case, two young boys who received gene therapy for the severe immunodeficiency disorder known as "bubble boy disease" developed leukemia-like symptoms 30 months after treatment. In this case, the viral vector inserted itself near a promoter region -- a site that initiates gene transcription -- of a proto-oncogene, a gene that can initiate cancer. Since viral vectors can integrate at various genomic locations, the safety and effectiveness of gene therapy ultimately depends on being able to predict a virus's particular bias.

In order to determine whether different viruses have greater gene therapy potential, Rick Mitchell et al. compared retroviral vectors derived from three viruses and report 3,127 sites where these viruses typically integrate into the human genome. The different vectors, they found, show different target preferences. Mitchell et al. studied vectors derived from the human immunodeficiency virus (HIV), avian sarcoma-leukosis virus (ASLV), and murine leukemia virus (MLV). Introducing the viral vectors into human cells, the authors analyzed the gene expression profiles of the cells to determine where vectors integrate into human chromosomes and which, if any, genes they activate. Each retrovirus, they discovered, showed distinct preferences for genome integration. HIV vectors tend to integrate into sites of active transcription, favoring chromosomal regions rich in expressed genes. MLV vectors tend to integrate near transcription initiation sites, confirming the results of a previous study, with a weak bias toward active genes. In contrast, the authors rep
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Contact: Paul Ocampo
pocampo@plos.org
1-415-624-1224
Public Library of Science
16-Aug-2004


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