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Journal of Virology, April 2009, p. 3704-3718, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.01384-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

O-Linked N-Acetylglucosaminylation of Sp1 Inhibits the Human Immunodeficiency Virus Type 1 Promoter{triangledown}

Ramona Jochmann,1 Mathias Thurau,1 Susan Jung,2 Christian Hofmann,3,4 Elisabeth Naschberger,1 Elisabeth Kremmer,5 Thomas Harrer,4 Matthew Miller,1 Niels Schaft,3 and Michael Stürzl1*

Division of Molecular and Experimental Surgery, Department of Surgery, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany,1 Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, Schlossgarten 4, 91054 Erlangen, Germany,2 Department of Dermatology, RNA Group, University Hospital of Erlangen, Hartmannstrasse 14, 91052 Erlangen, Germany,3 Department for Internal Medicine III with Institute for Clinical Immunology, University Hospital of Erlangen, Krankenhausstrasse 12, 91054 Erlangen, Germany,4 Institute of Molecular Immunology, Helmholtz Center Munich, Marchioninistrasse 25, 81377 Munich, Germany5

Received 2 July 2008/ Accepted 21 January 2009

Human immunodeficiency virus type 1 (HIV-1) gene expression and replication are regulated by the promoter/enhancer located in the U3 region of the proviral 5' long terminal repeat (LTR). The binding of cellular transcription factors to specific regulatory sites in the 5' LTR is a key event in the replication cycle of HIV-1. Since transcriptional activity is regulated by the posttranslational modification of transcription factors with the monosaccharide O-linked N-acetyl-D-glucosamine (O-GlcNAc), we evaluated whether increased O-GlcNAcylation affects HIV-1 transcription. In the present study we demonstrate that treatment of HIV-1-infected lymphocytes with the O-GlcNAcylation-enhancing agent glucosamine (GlcN) repressed viral transcription in a dose-dependent manner. Overexpression of O-GlcNAc transferase (OGT), the sole known enzyme catalyzing the addition of O-GlcNAc to proteins, specifically inhibited the activity of the HIV-1 LTR promoter in different T-cell lines and in primary CD4+ T lymphocytes. Inhibition of HIV-1 LTR activity in infected T cells was most efficient (>95%) when OGT was recombinantly overexpressed prior to infection. O-GlcNAcylation of the transcription factor Sp1 and the presence of Sp1-binding sites in the LTR were found to be crucial for this inhibitory effect. From this study, we conclude that O-GlcNAcylation of Sp1 inhibits the activity of the HIV-1 LTR promoter. Modulation of Sp1 O-GlcNAcylation may play a role in the regulation of HIV-1 latency and activation and links viral replication to the glucose metabolism of the host cell. Hence, the establishment of a metabolic treatment might supplement the repertoire of antiretroviral therapies against AIDS.

* Corresponding author. Mailing address: Division of Molecular and Experimental Surgery, Department of Surgery, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany. Phone: 49-9131-85-33109. Fax: 49-9131-85-32077. E-mail: michael.stuerzl{at}uk-erlangen.de

{triangledown} Published ahead of print on 4 February 2009.

Journal of Virology, April 2009, p. 3704-3718, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.01384-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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