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Journal of Virology, April 2005, p. 4479-4491, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.4479-4491.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1-Induced Macrophage Gene Expression Includes the p21 Gene, a Target for Viral Regulation

Nancy Vázquez,1* Teresa Greenwell-Wild,1 Nancy J. Marinos,1 William D. Swaim,1 Salvador Nares,1 David E. Ott,2 Ulrich Schubert,3,{dagger} Peter Henklein,4 Jan M. Orenstein,5 Michael B. Sporn,6 and Sharon M. Wahl1

Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research,1 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,3 Basic Research Program, SAIC Frederick, Inc., National Cancer Institute, Frederick, Maryland,2 Humboldt University, Berlin, Germany,4 George Washington University, Washington, D.C.,5 Dartmouth Medical School, Hanover, New Hampshire6

Received 17 March 2004/ Accepted 17 November 2004

In contrast to CD4+ T cells, human immunodeficiency virus type 1 (HIV-1)-infected macrophages typically resist cell death, support viral replication, and consequently, may facilitate HIV-1 transmission. To elucidate how the virus commandeers the macrophage's intracellular machinery for its benefit, we analyzed HIV-1-infected human macrophages for virus-induced gene transcription by using multiple parameters, including cDNA expression arrays. HIV-1 infection induced the transcriptional regulation of genes associated with host defense, signal transduction, apoptosis, and the cell cycle, among which the cyclin-dependent kinase inhibitor 1A (CDKN1A/p21) gene was the most prominent. p21 mRNA and protein expression followed a bimodal pattern which was initially evident during the early stages of infection, and maximum levels occurred concomitant with active HIV-1 replication. Mechanistically, viral protein R (Vpr) independently regulates p21 expression, consistent with the reduced viral replication and lack of p21 upregulation by a Vpr-negative virus. Moreover, the treatment of macrophages with p21 antisense oligonucleotides or small interfering RNAs reduced HIV-1 infection. In addition, the synthetic triterpenoid and peroxisome proliferator-activated receptor {gamma} ligand, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), which is known to influence p21 expression, suppressed viral replication. These data implicate p21 as a pivotal macrophage facilitator of the viral life cycle. Moreover, regulators of p21, such as CDDO, may provide an interventional approach to modulate HIV-1 replication.

* Corresponding author. Mailing address: NIH/NIDCR/OIIB, 30 Convent Dr., Bldg. 30, Rm. 332, MSC-4352, Bethesda, MD 20892. Phone: (301) 402-5101. Fax: (301) 402-1064. E-mail: nvazquez{at}mail.nih.gov.

{dagger} Present address: University of Erlangen-Nürnberg, Erlangen, Germany.

Journal of Virology, April 2005, p. 4479-4491, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.4479-4491.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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