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Antimicrobial Agents and Chemotherapy, May 2004, p. 1652-1663, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1652-1663.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Bis-Anthracycline Antibiotics Inhibit Human Immunodeficiency Virus Type 1 Transcription

Olaf Kutsch,^1* David N. Levy,² Paula J. Bates,³ Julie Decker,² Barry R. Kosloff,¹ George M. Shaw,^2,4 W. Priebe,⁵ and Etty N. Benveniste¹

Departments of Cell Biology,¹ Medicine, The University of Alabama at Birmingham,² The Howard Hughes Medical Institute, Birmingham, Alabama,⁴ The Department of Medicine, University of Louisville, Louisville, Kentucky,³ The University of Texas M. D. Anderson Cancer Center, Houston, Texas⁵

Received 26 August 2003/ Returned for modification 2 December 2003/ Accepted 8 January 2004

The increasing numbers of human immunodeficiency virus type 1 (HIV-1) strains that exhibit resistance to antiretroviral agents used at present require the development of new effective antiretroviral compounds. Tat transactivation was recognized early on as an attractive target for drug interference. To screen for and analyze the effects of compounds that interfere with Tat transactivation, we developed several cell-based reporter systems in which enhanced green fluorescence protein is a direct and quantitative marker of HIV-1 expression or Tat-dependent long terminal repeat activity. Using these reporter cell lines, we found that the bis-anthracycline WP631, a recently developed DNA intercalator, efficiently inhibits HIV-1 expression at subcytotoxic concentrations. WP631 also abrogated acute HIV-1 replication in peripheral blood mononuclear cells infected with various primary virus isolates. We demonstrate that WP631-mediated HIV-1 inhibition is caused by the inhibition of Tat transactivation. The data presented suggest that WP631 could serve as a lead compound for a new type of HIV-1 inhibitor.

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* Corresponding author. Present address: Division of Hematology/Oncology, University of Alabama at Birmingham, KAUL 840, 720 20th St. South, Birmingham, AL 35294. Phone: (205) 934-1547. Fax: (205) 934-1580. E-mail: okutsch{at}uab.edu.

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Antimicrobial Agents and Chemotherapy, May 2004, p. 1652-1663, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1652-1663.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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