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 HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Fletcher, P.
Right arrow Articles by Shattock, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fletcher, P.
Right arrow Articles by Shattock, R.

 Previous Article  |  Next Article 

Journal of Virology, September 2005, p. 11179-11186, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.11179-11186.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Nonnucleoside Reverse Transcriptase Inhibitor UC-781 Inhibits Human Immunodeficiency Virus Type 1 Infection of Human Cervical Tissue and Dissemination by Migratory Cells

Patricia Fletcher,1 Yana Kiselyeva,2 Greg Wallace,1 Joseph Romano,3 George Griffin,1 Leonid Margolis,2 and Robin Shattock1*

Division of Infectious Diseases, Cellular and Molecular Medicine, St George's, University of London, London, United Kingdom,1 Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland,2 Biosyn, Inc., Huntingdon Valley, Pennsylvania3

Received 14 December 2004/ Accepted 9 June 2005

Heterosexual transmission of human immunodeficiency virus remains the major route of transmission worldwide; thus, there is an urgent need for additional prevention strategies, particularly those that could be controlled by women. Using cellular and tissue explant models, we have evaluated the potential activity of thiocarboxanilide nonnucleoside analogue reverse transcriptase inhibitor UC-781 as a vaginal microbicide. We were able to demonstrate a potent dose-dependent effect against R5 and X4 infections of T cells. In human cervical explant cultures, UC-781 was not only able to inhibit direct infection of mucosal tissue but was able to prevent dissemination of virus by migratory cells. UC-781 formulated into a carbopol gel (0.1%) retained significant activity against both direct tissue infection and transinfection mediated by migratory cells. Furthermore, UC-781 demonstrated prolonged inhibitory effects able to prevent both localized and disseminated infections up to 6 days post compound treatment. Additional studies were carried out to determine the concentration of compound that might be required to block a primary infection within draining lymph nodes. While a greater dose of compound was required to inhibit both X4 and R5 infections of lymphoid versus cervical explants, this was equivalent to a 1:3,000 dilution of the 0.1% formulation. Furthermore, a 2-h exposure to the compound prevented infection of lymphoid tissue when challenged up to 2 days later. The prolonged protection observed following pretreatment of both genital and lymphoid tissues with UC-781 suggests that this class of inhibitors may have unique advantages over other classes of potential microbicide candidates.

* Corresponding author. Mailing address: Division of Infectious Diseases, Cellular and Molecular Medicine, St George's, University of London, Cranmer Terrace, Tooting, London SW17 0RE, United Kingdom. Phone: 011-44-208-725-5855. Fax: 011-44-208-725-3487. E-mail: shattock{at}sgul.ac.uk.

Journal of Virology, September 2005, p. 11179-11186, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.11179-11186.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Richardson-Harman, N., Lackman-Smith, C., Fletcher, P. S., Anton, P. A., Bremer, J. W., Dezzutti, C. S., Elliott, J., Grivel, J.-C., Guenthner, P., Gupta, P., Jones, M., Lurain, N. S., Margolis, L. B., Mohan, S., Ratner, D., Reichelderfer, P., Roberts, P., Shattock, R. J., Cummins, J. E. Jr. (2009). Multisite Comparison of Anti-Human Immunodeficiency Virus Microbicide Activity in Explant Assays Using a Novel Endpoint Analysis. J. Clin. Microbiol. 47: 3530-3539 [Abstract] [Full Text]  
  • Geuenich, S., Kaderali, L., Allespach, I., Sertel, S., Keppler, O. T. (2009). Biological Signature Characteristics of Primary Isolates from Human Immunodeficiency Virus Type 1 Group O in Ex Vivo Human Tonsil Histocultures. J. Virol. 83: 10494-10503 [Abstract] [Full Text]  
  • Herrera, C., Cranage, M., McGowan, I., Anton, P., Shattock, R. J. (2009). Reverse Transcriptase Inhibitors as Potential Colorectal Microbicides. Antimicrob. Agents Chemother. 53: 1797-1807 [Abstract] [Full Text]  
  • O'Keefe, B. R., Vojdani, F., Buffa, V., Shattock, R. J., Montefiori, D. C., Bakke, J., Mirsalis, J., d'Andrea, A.-L., Hume, S. D., Bratcher, B., Saucedo, C. J., McMahon, J. B., Pogue, G. P., Palmer, K. E. (2009). From the Cover: Scaleable manufacture of HIV-1 entry inhibitor griffithsin and validation of its safety and efficacy as a topical microbicide component. Proc. Natl. Acad. Sci. USA 106: 6099-6104 [Abstract] [Full Text]  
  • Fletcher, P., Harman, S., Azijn, H., Armanasco, N., Manlow, P., Perumal, D., de Bethune, M.-P., Nuttall, J., Romano, J., Shattock, R. (2009). Inhibition of Human Immunodeficiency Virus Type 1 Infection by the Candidate Microbicide Dapivirine, a Nonnucleoside Reverse Transcriptase Inhibitor. Antimicrob. Agents Chemother. 53: 487-495 [Abstract] [Full Text]  
  • Buffa, V., Stieh, D., Mamhood, N., Hu, Q., Fletcher, P., Shattock, R. J. (2009). Cyanovirin-N potently inhibits human immunodeficiency virus type 1 infection in cellular and cervical explant models. J. Gen. Virol. 90: 234-243 [Abstract] [Full Text]  
  • Terrazas-Aranda, K., Van Herrewege, Y., Hazuda, D., Lewi, P., Costi, R., Di Santo, R., Cara, A., Vanham, G. (2008). Human Immunodeficiency Virus Type 1 (HIV-1) Integration: a Potential Target for Microbicides To Prevent Cell-Free or Cell-Associated HIV-1 Infection. Antimicrob. Agents Chemother. 52: 2544-2554 [Abstract] [Full Text]  
  • Mesquita, P. M. M., Wilson, S. S., Manlow, P., Fischetti, L., Keller, M. J., Herold, B. C., Shattock, R. J. (2008). Candidate Microbicide PPCM Blocks Human Immunodeficiency Virus Type 1 Infection in Cell and Tissue Cultures and Prevents Genital Herpes in a Murine Model. J. Virol. 82: 6576-6584 [Abstract] [Full Text]  
  • Van Herrewege, Y., Morellato, L., Descours, A., Aerts, L., Michiels, J., Heyndrickx, L., Martin, L., Vanham, G. (2008). CD4 mimetic miniproteins: potent anti-HIV compounds with promising activity as microbicides. J Antimicrob Chemother 61: 818-826 [Abstract] [Full Text]  
  • Nuttall, J. P., Thake, D. C., Lewis, M. G., Ferkany, J. W., Romano, J. W., Mitchnick, M. A. (2008). Concentrations of Dapivirine in the Rhesus Macaque and Rabbit following Once Daily Intravaginal Administration of a Gel Formulation of [14C]Dapivirine for 7 Days. Antimicrob. Agents Chemother. 52: 909-914 [Abstract] [Full Text]  
  • Madan, R. P., Mesquita, P. M. M., Cheshenko, N., Jing, B., Shende, V., Guzman, E., Heald, T., Keller, M. J., Regen, S. L., Shattock, R. J., Herold, B. C. (2007). Molecular Umbrellas: a Novel Class of Candidate Topical Microbicides To Prevent Human Immunodeficiency Virus and Herpes Simplex Virus Infections. J. Virol. 81: 7636-7646 [Abstract] [Full Text]  
  • Cummins, J. E. Jr., Guarner, J., Flowers, L., Guenthner, P. C., Bartlett, J., Morken, T., Grohskopf, L. A., Paxton, L., Dezzutti, C. S. (2007). Preclinical Testing of Candidate Topical Microbicides for Anti-Human Immunodeficiency Virus Type 1 Activity and Tissue Toxicity in a Human Cervical Explant Culture. Antimicrob. Agents Chemother. 51: 1770-1779 [Abstract] [Full Text]  
  • D'Cruz, O. J., Uckun, F. M. (2006). Dawn of non-nucleoside inhibitor-based anti-HIV microbicides. J Antimicrob Chemother 57: 411-423 [Abstract] [Full Text]  


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