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Antimicrobial Agents and Chemotherapy, April 2009, p. 1490-1500, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01152-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Polyanionic Microbicides Modify Toll-Like Receptor-Mediated Cervicovaginal Immune Responses{triangledown}

R. T. Trifonova,1 G. F. Doncel,2 and R. N. Fichorova1*

Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,1 CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia 235072

Received 27 August 2008/ Returned for modification 7 November 2008/ Accepted 2 January 2009

Topical microbicides are being developed as a preventative approach to reduce the sexual transmission of human immunodeficiency virus type 1 (HIV-1) and other infections. For them to be efficacious, it is believed that they should avoid inducing inflammation while allowing the vaginal epithelium to initiate protective Toll-like receptor (TLR)-mediated innate responses against pathogens. In this study, human cervical and vaginal epithelial cells were exposed to polyanionic HIV entry inhibitors and the following synthetic TLR ligands: (i) the bacterial lipoprotein Pam3CSK4, binding cell surface TLR1/TLR2; (ii) macrophage activating lipopeptide 2 (MALP-2), binding cell surface TLR2/TLR6; and (iii) the viral double-stranded RNA analog poly(I:C), recognized by intracellular TLR3. Cell activation was assessed by nuclear factor {kappa}B (NF-{kappa}B) reporter gene transactivation and cytokine production. In spite of enhancing TLR-triggered NF-{kappa}B activation, the polyanionic microbicide compounds dextran sulfate and polystyrene sulfonate significantly inhibited TLR-mediated cytokine production. They decreased cytokine mRNA and protein levels of proinflammatory (interleukin-8 [IL-8] and IL-1β) and antiviral (beta interferon) cytokines following epithelial cell stimulation with Pam3CSK4, MALP-2, or poly(I:C). These activities were associated with the sulfate/sulfonate moieties of the polyanionic compounds, since the unsulfated dextran control did not show any effects. Our data demonstrate that these microbicide compounds are capable of selectively interfering with TLR-mediated epithelial responses at different points in their signaling pathways and underscore the importance of expanding the assessment of microbicide compatibility with vaginal innate immune function. Further studies are warranted to determine the impact of this interference on HIV-1 transmission risk.

* Corresponding author. Mailing address: Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, 221 Longwood Ave., RF468, Boston, MA 02115. Phone: (617) 278-0625. Fax: (617) 713-3018. E-mail: rfichorova{at}rics.bwh.harvard.edu

{triangledown} Published ahead of print on 12 January 2009.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1490-1500, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01152-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sonza, S., Johnson, A., Tyssen, D., Spelman, T., Lewis, G. R., Paull, J. R. A., Tachedjian, G. (2009). Enhancement of Human Immunodeficiency Virus Type 1 Replication Is Not Intrinsic to All Polyanion-Based Microbicides. Antimicrob. Agents Chemother. 53: 3565-3568 [Abstract] [Full Text]  


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