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Human T-Cell Leukemia Virus Type 1 Integration Target Sites in the Human Genome: Comparison with Those of Other Retroviruses ^,

David Derse,^1, Bruce Crise,^2, Yuan Li,³ Gerald Princler,¹ Nicole Lum,⁴ Claudia Stewart,⁴ Connor F. McGrath,⁵ Stephen H. Hughes,¹ David J. Munroe,⁴ and Xiaolin Wu^4*

HIV Drug Resistance Program, NCI-Frederick, Frederick, Maryland 21702,¹ Gene Expression Laboratory,² AIDS Vaccine Program,³ Laboratory of Molecular Technology,⁴ Target Structure-Based Drug Discovery Group, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702⁵

Received 14 December 2006/ Accepted 29 March 2007

Retroviral integration into the host genome is not entirely random, and integration site preferences vary among different retroviruses. Human immunodeficiency virus (HIV) prefers to integrate within active genes, whereas murine leukemia virus (MLV) prefers to integrate near transcription start sites and CpG islands. On the other hand, integration of avian sarcoma-leukosis virus (ASLV) shows little preference either for genes, transcription start sites, or CpG islands. While host cellular factors play important roles in target site selection, the viral integrase is probably the major viral determinant. It is reasonable to hypothesize that retroviruses with similar integrases have similar preferences for target site selection. Although integration profiles are well defined for members of the lentivirus, spumaretrovirus, alpharetrovirus, and gammaretrovirus genera, no members of the deltaretroviruses, for example, human T-cell leukemia virus type 1 (HTLV-1), have been evaluated. We have mapped 541 HTLV-1 integration sites in human HeLa cells and show that HTLV-1, like ASLV, does not specifically target transcription units and transcription start sites. Comparing the integration sites of HTLV-1 with those of ASLV, HIV, simian immunodeficiency virus, MLV, and foamy virus, we show that global and local integration site preferences correlate with the sequence/structure of virus-encoded integrases, supporting the idea that integrase is the major determinant of retroviral integration site selection. Our results suggest that the global integration profiles of other retroviruses could be predicted from phylogenetic comparisons of the integrase proteins. Our results show that retroviruses that engender different insertional mutagenesis risks can have similar integration profiles.

Published ahead of print on 4 April 2007.

Supplemental material for this article may be found at http://jvi.asm.org/.

These authors contributed equally to this work.

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