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Journal of Virology, April 2003, p. 4025-4032, Vol. 77, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.7.4025-4032.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Transcriptional Suppression of In Vitro-Integrated Human Immunodeficiency Virus Type 1 Does Not Correlate with Proviral DNA Methylation

Marjorie Pion,1,{dagger} Albert Jordan,2 Angelique Biancotto,1 Franck Dequiedt,2 Françoise Gondois-Rey,1 Sophie Rondeau,1 Robert Vigne,1 Jiri Hejnar,3 Eric Verdin,2 and Ivan Hirsch1*

INSERM U372, Unité de Pathogénie des Infections à Lentivirus, Parc Scientifique et Technologique de Luminy, 13276 Marseille, France,1 Gladstone Institute of Virology and Immunology, San Francisco, California 94141,2 Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 166 37 Prague, Czech Republic3

Received 30 September 2002/ Accepted 3 January 2003

Persistence of human immunodeficiency virus type 1 (HIV-1) constitutes a major obstacle in the control of HIV-1 infection. Here we investigated whether the CpG methylation of the HIV-1 promoter can directly influence the expression of the HIV-1 genome and thereby contribute to the persistence and latency of HIV-1. The levels of CpG methylation in the promoter of HIV-1 were studied after bisulfite-induced modification of DNA in five Jurkat clonal cell lines transduced by an HIV-1 long terminal repeat (LTR)-driven retroviral vector and expressing enhanced green fluorescent protein (GFP) and in primary resting memory T cells challenged with HIV-1 or with an HIV-1-derived retroviral vector. Basal HIV-1 promoter activities were low or undetectable in three tested HIV-1 LTR-GFP clones, one of which encoded the Tat protein, and they reached medium or high levels in two other clones. The CpG dinucleotide that occurred in a latently infected clonal cell line 240 nucleotides upstream of the transcription start remained methylated after reactivation of HIV-1 transcription with 10 nM phorbol-12-myristate-13-acetate. In two clones showing a medium promoter activity and in resting memory T cells, the HIV-1 LTR was generally not methylated. Our results show that the methylation profiles of the HIV-1 LTR, including those present in latently infected cells, are low and do not correlate with the transcriptional activity. We suggest that, in a noncloned cellular population in which the HIV-1 proviruses are randomly integrated in the human genome, HIV-1 latency is imperfectly controlled by CpG methylation and is inherently accompanied by residual replication.

* Corresponding author. Mailing address: INSERM U372, Laboratoire de Pathogenie des Infections à Lentivirus, 163 Avenue de Luminy, B.P. 178, 13276 Marseille Cedex 9, France. Phone: (33) 4 91 82 75 85. Fax: (33) 4 91 82 60 61. E-mail: ihirsch{at}inserm-u372.univ-mrs.fr.

{dagger} Present address: Department of Dermatology, University of Geneva, HUG, 1211 Geneva, Switzerland.

Journal of Virology, April 2003, p. 4025-4032, Vol. 77, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.7.4025-4032.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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