This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rabaaoui, S.
Right arrow Articles by Wattel, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rabaaoui, S.
Right arrow Articles by Wattel, E.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, October 2008, p. 3532-3541, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.01361-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Inhibitors of Strand Transfer That Prevent Integration and Inhibit Human T-Cell Leukemia Virus Type 1 Early Replication{triangledown}

Samira Rabaaoui,1 Fatima Zouhiri,2 Agnès Lançon,1 Hervé Leh,2 Jean d'Angelo,3 and Eric Wattel1,4*

CNRS UMR5537, Université Lyon 1, Centre Léon Bérard, Oncovirologie et Biothérapies, 28 rue Laënnec, 69373, Lyon Cedex 08, France,1 BioAlliance Pharma SA, 59 bd. du Général Martial Valin, 75015 Paris, France,2 CNRS, UMR 8076, Unité Associée, Faculté de Pharmacie, 5 rue J.-B. Clément, 92290 Châtenay-Malabry, France,3 Hôpital Edouard Herriot, Service d'Hématologie, Pavillon E, Lyon, France4

Received 23 October 2007/ Returned for modification 31 December 2007/ Accepted 25 February 2008

The replication of the retrovirus human T-cell leukemia virus type 1 (HTLV-1) is linked to the development of lymphoid malignancies and inflammatory diseases. Data from in vitro, ex vivo, and in vivo studies have revealed that no specific treatment can prevent or block HTLV-1 replication and therefore that there is no therapy for the prevention and/or treatment of HTLV-1-associated diseases in infected individuals. HTLV-1 and human immunodeficiency virus type 1 (HIV-1) integrases, the enzymes that specifically catalyze the integration of these retroviruses in host cell DNA, share important structural properties, suggesting that compounds that inhibit HIV-1 integration could also inhibit HTLV-1 integration. We developed quantitative assays to test, in vitro and ex vivo, the efficiencies of styrylquinolines and diketo acids, the two main classes of HIV-1 integrase inhibitors. The compounds were tested in vitro in an HTLV-1 strand-transfer reaction and ex vivo by infection of fresh peripheral blood lymphocytes with lethally irradiated HTLV-1-positive cells. In vitro, four styrylquinoline compounds and two diketo acid compounds significantly inhibited HTLV-1 integration in a dose-dependent manner. All compounds active in vitro decreased cell proliferation ex vivo, although at low concentrations; they also dramatically decreased both normalized proviral loads and the number of integration events during experimental ex vivo primary infection. Accordingly, diketo acids and styrylquinolines are the first drugs that produce a specific negative effect on HTLV-1 replication in vitro and ex vivo, suggesting their potential efficiency for the prevention and treatment of HTLV-1-associated diseases.

* Corresponding author. Mailing address: Oncovirologie et Biothérapies, UMR5537-CNRS, Université Claude Bernard, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cedex 08, France. Phone: 33 4 78 78 26 69. Fax: 33 4 78 78 27 17. E-mail: wattel{at}lyon.fnclcc.fr

{triangledown} Published ahead of print on 3 March 2008.

Antimicrobial Agents and Chemotherapy, October 2008, p. 3532-3541, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.01361-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»