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Journal of Virology, July 2008, p. 6591-6599, Vol. 82, No. 13
0022-538X/08/$08.00+0     doi:10.1128/JVI.02730-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Incomplete Protection against Simian Immunodeficiency Virus Vaginal Transmission in Rhesus Macaques by a Topical Antiviral Agent Revealed by Repeat Challenges{triangledown}

Zandrea Ambrose,1* Lara Compton,2 Michael Piatak Jr.,3 Ding Lu,2 W. Gregory Alvord,4 Mariusz S. Lubomirski,4 James E. K. Hildreth,5 Jeffrey D. Lifson,3 Christopher J. Miller,2 and Vineet N. KewalRamani1*

HIV Drug Resistance Program, National Cancer Institute, Frederick, Maryland 21702,1 California National Primate Research Center and Center for Comparative Medicine, University of California at Davis, Davis, California 95616,2 AIDS Vaccine Program, SAIC Frederick, Inc., National Cancer Institute, Frederick, Maryland 21702,3 Data Management Services, Inc., National Cancer Institute, Frederick, Maryland 21702,4 Meharry Medical College, Nashville, Tennessee 372085

Received 29 December 2007/ Accepted 11 April 2008

The rising prevalence of human immunodeficiency virus type 1 (HIV-1) infection in women, especially in resource-limited settings, accentuates the need for accessible, inexpensive, and female-controlled preexposure prophylaxis strategies to prevent mucosal transmission of the virus. While many compounds can inactivate HIV-1 in vitro, evaluation in animal models for mucosal transmission of virus may help identify which approaches will be effective in vivo. Macaques challenged intravaginally with pathogenic simian immunodeficiency virus (SIVmac251) provide a model to preclinically evaluate candidate microbicides. 2-Hydroxypropyl-β-cyclodextrin (BCD) prevents HIV-1 and SIV infection of target cells at subtoxic doses in vitro. Consistent with these findings, intravaginal challenge of macaques with SIVmac251 preincubated with BCD prevented mucosal transmission, as measured by plasma viremia and antiviral antibodies, through 10 weeks postchallenge. In an initial challenge, BCD applied topically prior to SIVmac251 prevented intravaginal transmission of virus compared to controls (P < 0.0001). However, upon a second virus challenge following BCD pretreatment, the majority of the previously protected animals became infected. The mechanism through which animals become infected at a frequency similar to that of controls after prior exposure to BCD and SIVmac251 in subsequent intravaginal virus challenges (P = 0.63), despite the potent antiviral properties of BCD, remains to be determined. These results highlight the unpredictability of antiviral compounds as topical microbicides and suggest that repeated exposures to candidate treatments should be considered for in vivo evaluation.

* Corresponding author. Present address for Z. Ambrose: Division of Infectious Diseases, 817B Scaife Hall, University of Pittsburgh, Pittsburgh, PA 15261. Phone: (412) 624-0512. Fax: (412) 648-8521. E-mail: ambrosez{at}dom.pitt.edu. Mailing address for V. N. KewalRamani: HIV Drug Resistance Program, National Cancer Institute, Building 535, Room 108, Frederick, MD 21702. Phone: (301) 846-1249. Fax: (301) 846-6777. E-mail: vineet{at}ncifcrf.gov

{triangledown} Published ahead of print on 23 April 2008.

Journal of Virology, July 2008, p. 6591-6599, Vol. 82, No. 13
0022-538X/08/$08.00+0     doi:10.1128/JVI.02730-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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