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Antimicrobial Agents and Chemotherapy, February 2009, p. 487-495, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01156-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Inhibition of Human Immunodeficiency Virus Type 1 Infection by the Candidate Microbicide Dapivirine, a Nonnucleoside Reverse Transcriptase Inhibitor

P. Fletcher,¹ S. Harman,¹ H. Azijn,² N. Armanasco,¹ P. Manlow,¹ D. Perumal,^1, M.-P. de Bethune,² J. Nuttall,³ J. Romano,³ and R. Shattock^1*

St George's University of London, London, United Kingdom,¹ Tibotec BVBA, Mechelen, Belgium,² International Partnership for Microbicides, Silver Spring, MD³

Received 28 August 2008/ Returned for modification 3 October 2008/ Accepted 13 November 2008

Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.

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* Corresponding author. Mailing address: Centre for Infection, Cellular and Molecular Medicine, St George's, University of London, Cranmer Terrace, Tooting, London SW17 0RE, United Kingdom. Phone: 44 (208) 725-5855. Fax: 44 (208) 725-3487. E-mail: shattock{at}sgul.ac.uk

Published ahead of print on 24 November 2008.

Present address: London Metropolitan University, London, United Kingdom.

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Antimicrobial Agents and Chemotherapy, February 2009, p. 487-495, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01156-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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