Semen enhances HIV infectivity and impairs the antiviral efficacy of microbicides

Topically applied microbicides potently inhibit HIV in vitro but have largely failed to exert protective effects in clinical trials. One possible reason for this discrepancy is that the preclinical testing of microbicides does not faithfully reflect the conditions of HIV sexual transmission. We repo...

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Bibliographic Details
Published inScience translational medicine Vol. 6; no. 262; p. 262ra157
Main Authors Zirafi, Onofrio, Kim, Kyeong-Ae, Roan, Nadia R, Kluge, Silvia F, Müller, Janis A, Jiang, Shibo, Mayer, Benjamin, Greene, Warner C, Kirchhoff, Frank, Münch, Jan
Format Journal Article
LanguageEnglish
Published United States 12.11.2014
Subjects
Anti-HIV Agents - pharmacology
Anti-Infective Agents - pharmacology
Cell Line
Cell Line, Tumor
Cell Survival
Dendrimers - pharmacology
Female
HIV Infections - drug therapy
HIV Infections - prevention & control
HIV-1 - pathogenicity
Humans
Inhibitory Concentration 50
Polylysine - pharmacology
Semen - chemistry
Semen - virology
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Summary:Topically applied microbicides potently inhibit HIV in vitro but have largely failed to exert protective effects in clinical trials. One possible reason for this discrepancy is that the preclinical testing of microbicides does not faithfully reflect the conditions of HIV sexual transmission. We report that candidate microbicides that target HIV components show greatly reduced antiviral efficacy in the presence of semen, the main vector for HIV transmission. This diminished antiviral activity was dependent on the ability of amyloid fibrils in semen to enhance the infectivity of HIV. Thus, the anti-HIV efficacy of microbicides determined in the absence of semen greatly underestimated the drug concentrations needed to block semen-exposed virus. One notable exception was maraviroc. This HIV entry inhibitor targets the host cell CCR5 co-receptor and was highly active against both untreated and semen-exposed HIV. These data help to explain why microbicides have failed to protect against HIV in clinical trials and suggest that antiviral compounds targeting host factors hold promise for further development. These findings also suggest that the in vitro efficacy of candidate microbicides should be determined in the presence of semen to identify the best candidates for the prevention of HIV sexual transmission.
ISSN:1946-6242
DOI:10.1126/scitranslmed.3009634