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Antimicrobial Agents and Chemotherapy, May 2009, p. 1797-1807, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01096-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Reverse Transcriptase Inhibitors as Potential Colorectal Microbicides{triangledown} ,{dagger}

Carolina Herrera,1 Martin Cranage,1 Ian McGowan,2 Peter Anton,3 and Robin J. Shattock1*

Division of Cellular and Molecular Medicine, St George's University of London, London, United Kingdom,1 Magee-Women's Research Institute, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania,2 Center for HIV Prevention Research, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California3

Received 14 August 2008/ Returned for modification 16 October 2008/ Accepted 12 February 2009

We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.

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

{triangledown} Published ahead of print on 2 March 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, May 2009, p. 1797-1807, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01096-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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