Transcription Start Regions in the Human Genome Are Favored Targets for MLV Integration

Factors contributing to retroviral integration have been intractable because past studies have not precisely located genomic sites of proviruses in sufficient numbers for significant analysis. In this study, 903 murine leukemia virus (MLV) and 379 human immunodeficiency virus–1 (HIV-1) integrations in the human genome were mapped. The data showed that MLV preferred integration near the start of transcriptional units (either upstream or downstream) whereas HIV-1 preferred integration anywhere in the transcriptional unit but not upstream of the transcriptional start. Defining different integration site preferences for retroviruses will have important ramifications for gene therapy and may aid in our understanding of the factors directing the integration process.

[1]  F. Bushman.  Tethering human immunodeficiency virus 1 integrase to a DNA site directs integration to nearby sequences. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[2]  A. Fischer,et al.  Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. , 2002, The New England journal of medicine.

[3]  K. Katz,et al.  Introducing RefSeq and LocusLink: curated human genome resources at the NCBI. , 2000, Trends in genetics : TIG.

[4]  J. Weidhaas,et al.  Relationship between Retroviral DNA Integration and Gene Expression , 2000, Journal of Virology.

[5]  Paul Shinn,et al.  HIV-1 Integration in the Human Genome Favors Active Genes and Local Hotspots , 2002, Cell.

[6]  K. Harbers,et al.  Retroviral integration sites in transgenic Mov mice frequently map in the vicinity of transcribed DNA regions , 1990, Journal of virology.

[7]  J. Kaiser.  Seeking the Cause of Induced Leukemias in X-SCID Trial , 2003, Science.

[8]  H. Varmus,et al.  Retroviral integration into minichromosomes in vitro. , 1992, The EMBO journal.

[9]  Erika Check,et al.  Gene therapy: A tragic setback , 2002, Nature.

[10]  H. Varmus,et al.  Simian virus 40 minichromosomes as targets for retroviral integration in vivo. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[11]  F. Deist,et al.  Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. , 2000, Science.

[12]  F. Bushman,et al.  The influence of DNA and nucleosome structure on integration events directed by HIV integrase. , 1994, The Journal of biological chemistry.

[13]  F. Bushman,et al.  Human immunodeficiency virus integrase directs integration to sites of severe DNA distortion within the nucleosome core. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[14]  A. Bird.  CpG-rich islands and the function of DNA methylation , 1986, Nature.

[15]  M. Breindl,et al.  Transcriptionally active genome regions are preferred targets for retrovirus integration , 1990, Journal of virology.

[16]  Harold E. Varmus,et al.  Nucleosomes, DNA-binding proteins, and DNA sequence modulate retroviral integration target site selection , 1992, Cell.

[17]  H. Prydz,et al.  CpG islands as gene markers in the human genome. , 1992, Genomics.