1. Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cells.
- Author
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Hematti P, Hong BK, Ferguson C, Adler R, Hanawa H, Sellers S, Holt IE, Eckfeldt CE, Sharma Y, Schmidt M, von Kalle C, Persons DA, Billings EM, Verfaillie CM, Nienhuis AW, Wolfsberg TG, Dunbar CE, and Calmels B
- Subjects
- Animals, Antigens, CD34 biosynthesis, Binding Sites, Cell Line, Cloning, Molecular, Cluster Analysis, DNA Primers chemistry, Gene Transfer Techniques, Macaca mulatta, Molecular Sequence Data, Mutation, Polymerase Chain Reaction, Retroviridae genetics, Time Factors, Transcription, Genetic, Genetic Vectors, Genome, Hematopoietic Stem Cells virology, Leukemia Virus, Murine metabolism, Simian Immunodeficiency Virus metabolism, Stem Cells virology
- Abstract
Murine leukemia virus (MLV)-derived vectors are widely used for hematopoietic stem cell (HSC) gene transfer, but lentiviral vectors such as the simian immunodeficiency virus (SIV) may allow higher efficiency transfer and better expression. Recent studies in cell lines have challenged the notion that retroviruses and retroviral vectors integrate randomly into their host genome. Medical applications using these vectors are aimed at HSCs, and thus large-scale comprehensive analysis of MLV and SIV integration in long-term repopulating HSCs is crucial to help develop improved integrating vectors. We studied integration sites in HSCs of rhesus monkeys that had been transplanted 6 mo to 6 y prior with MLV- or SIV-transduced CD34(+)cells. Unique MLV (491) and SIV (501) insertions were compared to a set of in silico-generated random integration sites. While MLV integrants were located predominantly around transcription start sites, SIV integrants strongly favored transcription units and gene-dense regions of the genome. These integration patterns suggest different mechanisms for integration as well as distinct safety implications for MLV versus SIV vectors., Competing Interests: The authors have declared that no conflicts of interest exist.
- Published
- 2004
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