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Journal of Virology, June 2005, p. 6610-6619, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6610-6619.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Genome-Wide Analysis of Chromosomal Features Repressing Human Immunodeficiency Virus Transcription{dagger}

M. K. Lewinski,1 D. Bisgrove,2 P. Shinn,3 H. Chen,3 C. Hoffmann,4 S. Hannenhalli,5 E. Verdin,2 C. C. Berry,6 J. R. Ecker,3 and F. D. Bushman1,4*

Infectious Disease Laboratory, The Salk Institute, 10010 North Torrey Pines Rd., La Jolla, California 92037,1 University of Pennsylvania School of Medicine, Department of Microbiology, 3610 Hamilton Walk, Philadelphia, Pennsylvania 19104-6076,4 Gladstone Institute of Virology and Immunology, University of California, San Francisco, 365 Vermont Street, San Francisco, California 94103,2 Genomic Analysis Laboratory, The Salk Institute, 10010 North Torrey Pines Rd., La Jolla, California 92037,3 Department of Family/Preventive Medicine, University of California, San Diego School of Medicine, San Diego, California 92093,6 University of Pennsylvania School of Medicine, 1409 Blockley Hall, 423 Guardian Drive, Philadelphia, Pennsylvania 19104-60765

Received 19 November 2004/ Accepted 20 January 2005

We have investigated regulatory sequences in noncoding human DNA that are associated with repression of an integrated human immunodeficiency virus type 1 (HIV-1) promoter. HIV-1 integration results in the formation of precise and homogeneous junctions between viral and host DNA, but integration takes place at many locations. Thus, the variation in HIV-1 gene expression at different integration sites reports the activity of regulatory sequences at nearby chromosomal positions. Negative regulation of HIV transcription is of particular interest because of its association with maintaining HIV in a latent state in cells from infected patients. To identify chromosomal regulators of HIV transcription, we infected Jurkat T cells with an HIV-based vector transducing green fluorescent protein (GFP) and separated cells into populations containing well-expressed (GFP-positive) or poorly expressed (GFP-negative) proviruses. We then determined the chromosomal locations of the two classes by sequencing 971 junctions between viral and cellular DNA. Possible effects of endogenous cellular transcription were characterized by transcriptional profiling. Low-level GFP expression correlated with integration in (i) gene deserts, (ii) centromeric heterochromatin, and (iii) very highly expressed cellular genes. These data provide a genome-wide picture of chromosomal features that repress transcription and suggest models for transcriptional latency in cells from HIV-infected patients.

* Corresponding author. Mailing address: Department of Microbiology, University of Pennsylvania School of Medicine, 402C Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104-6076. Phone: (215) 573-8732. Fax: (215) 573-4856. E-mail: bushman{at}mail.med.upenn.edu.

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

Journal of Virology, June 2005, p. 6610-6619, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6610-6619.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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