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Journal of Virology, November 2005, p. 14355-14370, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.14355-14370.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Toll-Like Receptor 7 (TLR7) Agonist, Imiquimod, and the TLR9 Agonist, CpG ODN, Induce Antiviral Cytokines and Chemokines but Do Not Prevent Vaginal Transmission of Simian Immunodeficiency Virus When Applied Intravaginally to Rhesus Macaques

Yichuan Wang,1,2 Kristina Abel,1,2,3 Katherine Lantz,1,2 Arthur M. Krieg,5 Michael B. McChesney,1 and Christopher J. Miller1,2,3,4*

California National Primate Research Center,1 Center for Comparative Medicine,2 Division of Infectious Diseases, School of Medicine,3 Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California-Davis, Davis, California 95616,4 Coley Pharmaceutical Group, Inc., Wellesley, Massachusetts5

Received 29 June 2005/ Accepted 16 August 2005

The initial host response to viral infection occurs after Toll-like receptors (TLRs) on dendritic cells (DC) are stimulated by viral nucleic acids (double-stranded RNA, single-stranded RNA) and alpha interferon (IFN-{alpha}) and IFN-ß are produced. We hypothesized that pharmacologic induction of innate antiviral responses in the cervicovaginal mucosa by topical application of TLR agonists prior to viral exposure could prevent or blunt vaginal transmission of simian immunodeficiency virus (SIV). To test this hypothesis, we treated rhesus monkeys intravaginally with either the TLR9 agonist, CpG oligodeoxynucleotides (ODN), or the TLR7 agonist, imiquimod. Both immune modifiers rapidly induced IFN-{alpha} and other antiviral effector molecules in the cervicovaginal mucosa of treated animals. However, both CpG ODN and imiquimod also induced proinflammatory cytokine expression in the cervicovaginal mucosa. In the vaginal mucosa of imiquimod-treated monkeys, we documented a massive mononuclear cell infiltrate consisting of activated CD4+ T cells, DC, and beta-chemokine-secreting cells. After vaginal SIV inoculation, all TLR agonist-treated animals became infected and had plasma vRNA levels that were higher than those of control monkeys. We conclude that induction of mucosal innate immunity including an IFN-{alpha} response is not sufficient to prevent sexual transmission of human immunodeficiency virus.

* Corresponding author. Mailing address: UC Davis, CNPRC/CCM, One Shields Ave., Davis, CA 95616. Phone: (530) 752-1229. Fax: (530) 754-4411. E-mail: cjmiller{at}ucdavis.edu.

Journal of Virology, November 2005, p. 14355-14370, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.14355-14370.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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