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Unique Collaboration Charts the Migrations of a Parasite that Affected History
Researchers Sequence Louse DNA from Mummies and Propose New Model for its Development


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1 January 2006

Volume 193, Number 1
The Journal of Infectious Diseases 2006;193:27–35
0022-1899/2006/19301-0006$15.00
DOI: 10.1086/498533
MAJOR ARTICLE

PRO 2000 Gel Inhibits HIV and Herpes Simplex Virus Infection Following Vaginal Application: A Double-Blind Placebo-Controlled Trial

Marla J. Keller,1

Bouchra Zerhouni-Layachi,1

Natalia Cheshenko,2

Minnie John,2

Kathleen Hogarty,1

Andrea Kasowitz,1

Cindy L. Goldberg,2

Sylvan Wallenstein,3

Albert T. Profy,4

Mary E. Klotman,1 and

Betsy C. Herold2

Departments of 1Medicine, 2Pediatrics, and 3Community Medicine, Mount Sinai School of Medicine, New York, New York; 4Indevus Pharmaceuticals, Lexington, Massachusetts

Background.  Microbicides used to prevent the transmission of human immunodeficiency virus (HIV) are advancing to clinical trials on the basis of activity observed in vitro and in animal models. However, no data demonstrate activity of microbicides after application in humans. This study was designed to determine the antiviral activity in cervicovaginal lavage (CVL) samples collected after intravaginal application of 0.5% PRO 2000 gel (Indevus).

Methods.  A randomized, double-blind study was conducted to assess the anti-HIV and anti–herpes simplex virus (HSV) activity of PRO 2000 in CVL samples obtained at screening (48 hours before) and 1 hour after application of study or placebo gel. HeLa cells or human macrophages were inoculated with CVL samples spiked with replication-defective HIV containing a luciferase indicator gene and pseudotyped with an R5 envelope. Human cervical epithelial cells were inoculated with CVL samples and challenged with HSV-2(G), and the virus titer was then determined.

Results.  CVL samples obtained after application of PRO 2000 gel significantly inhibited HIV and HSV infection by at least 1000-fold, compared with CVL samples obtained at screening ( ). There were no differences in cytokine levels between the drug and placebo groups.

Conclusions.  PRO 2000 gel (0.5%) is sufficiently bioavailable and retains substantial antiviral activity after intravaginal application. This strategy provides a mechanism for testing the efficacy of a microbicide before embarking on large-scale clinical trials.

Received 17 May 2005; accepted 21 July 2005; electronically published 17 November 2005.

Reprints or correspondence: Dr. Betsy C. Herold, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1657, New York, NY 10029 ().

Cited by

Mary Poynten, Joelle M Brown, Monica Sovero, Iona Y Millwood, John M Kaldor. (2008) Microbicide safety and effectiveness: an overview of recent clinical trials. Current Opinion in HIV and AIDS 3:5, 574-580
Online publication date: 1-Oct-2008.
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Diana G. Scorpio, Dawn S. Ruben, Zhaohao Liao, James E. Hildreth, Craig A. Fletcher. (2008) Cervicovaginal evaluation in macaques used as a model for topical microbicide safety studies. Journal of Medical Primatology 37:s1, 65-73
Online publication date: 1-Mar-2008.
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Lisa C. Rohan, Sharon L. Hillier, and Charlene S. Dezzutti. (2007) Preventing the Sexual Transmission of HIV-1 with Topical Microbicides: Another Piece of the Equation. The Journal of Infectious Diseases 196:9, 1285-1287
Online publication date: 1-Nov-2007.
Sarju Patel, Ehsan Hazrati, Natalia Cheshenko, Benjamin Galen, Heyi Yang, Esmeralda Guzman, Rong Wang, Betsy C. Herold, and Marla J. Keller. (2007) Seminal Plasma Reduces the Effectiveness of Topical Polyanionic Microbicides. The Journal of Infectious Diseases 196:9, 1394-1402
Online publication date: 1-Nov-2007.
Joelle M Brown, Anna Wald, Alan Hubbard, Kittipong Rungruengthanakit, Tsungai Chipato, Sungwal Rugpao, Francis Mmiro, David D Celentano, Robert S Salata, Charles S Morrison, Barbra A Richardson, Nancy S Padian. (2007) Incident and prevalent herpes simplex virus type 2 infection increases risk of HIV acquisition among women in Uganda and Zimbabwe. AIDS 21:12, 1515-1523
Online publication date: 1-Aug-2007.
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Benjamin T. Galen, Andrea P. Martin, Ehsan Hazrati, Alexandre Garin, Esmeralda Guzman, Sarah S. Wilson, David D. Porter, Sergio A. Lira, Marla J. Keller, and Betsy C. Herold. (2007) A Comprehensive Murine Model to Evaluate Topical Vaginal Microbicides: Mucosal Inflammation and Susceptibility to Genital Herpes as Surrogate Markers of Safety. The Journal of Infectious Diseases 195:9, 1332-1339
Online publication date: 1-May-2007.
Marla J Keller, Esmeralda Guzman, Ehsan Hazrati, Andrea Kasowitz, Natalia Cheshenko, Sylvan Wallenstein, Amy L Cole, Alexander M Cole, Albert T Profy, Charles R Wira, Kathleen Hogarty, Betsy C Herold. (2007) PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity. AIDS 21:4, 467???476
Online publication date: 1-Mar-2007.
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Damjan S Nikolic, Eduardo Garcia, Vincent Piguet. (2007) Microbicides and other topical agents in the prevention of HIV and sexually transmitted infections. Expert Review of Anti-infective Therapy 5:1, 77
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Marla J. Keller, Betsy C. Herold. (2006) Impact of Microbicides and Sexually Transmitted Infections on Mucosal Immunity in the Female Genital Tract. American Journal of Reproductive Immunology 56:5-6, 356-363
Online publication date: 1-Dec-2006.
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Darpun Dhawan and Kenneth H. Mayer. (2006) Microbicides to Prevent HIV Transmission: Overcoming Obstacles to Chemical Barrier Protection. The Journal of Infectious Diseases 193:1, 36-44
Online publication date: 1-Jan-2006.
  • Presented in part: Microbicides 2004, London, 30 March 2004 (oral presentation 02603); 12th Conference on Retroviruses and Opportunistic Infections, Boston, 24 February 2005 (abstract 535).

    Financial support: National Institutes of Health (grants HD-43733 and RR-00071 and training grant AI-07623 to M.J.).

    Potential conflicts of interest: A.T.P. is a full-time employee of Indevus Pharmaceuticals, the developers of PRO 2000 gel, and holds equity interest in the company. All other authors: none reported.

  • (See the article by Dhawan and Mayer, on pages 36–44.)

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