title: Antiviral and immunological effects of tenofovir microbicide in vaginal herpes simplex virus 2 infection.
abstract: The anti-HIV microbicide, tenofovir (TFV) gel, has been shown to decrease HIV-1 acquisition by 39% and reduce herpes simplex virus 2 (HSV-2) transmission by 51%. We evaluated the effect of a 1% TFV gel on genital HSV-2 infection in a mouse vaginal challenge model. In vitro plaque assays and luminex multiplex bead analysis were used, respectively, to measure postinfection vaginal viral shedding (day 1) and cytokine secretion (day 2). To further investigate the anti-HSV-2 properties, we evaluated the direct antiviral effect of TFV and the oral prodrug tenofovir disoproxil fumerate (TDF) in cell culture. Compared to placebo-treated mice, TFV-treated mice had significantly lower clinical scores, developed later genital lesions, and showed reduced vaginal viral shedding. Furthermore, the levels of IFN-γ, IL-2, TNF-α, and other cytokines were altered in the vaginal fluid following topical tenofovir treatment and subsequent HSV-2 challenge. Finally, we found that both TFV and TDF inhibited HSV-2 infection in vitro; TDF showed a 50-fold greater potency than TFV. In conclusion, we confirmed that the microbicide TFV had direct anti-HSV-2 effects in a murine vaginal challenge model. Therefore, this model would be suitable for evaluating present and future microbicide candidates. Furthermore, the present study warrants further investigation of TDF in microbicides.
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital , Aarhus, Denmark.
authors.forename: Line
authors.initials: L
authors.lastname: Vibholm
authors.forename: Line S
authors.initials: LS
authors.lastname: Reinert
authors.forename: Ole S
authors.initials: OS
authors.lastname: Søgaard
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
authors.forename: Lars
authors.initials: L
authors.lastname: Østergaard
authors.forename: Martin
authors.initials: M
authors.lastname: Tolstrup
authors.forename: Jesper
authors.initials: J
authors.lastname: Melchjorsen
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D000287:Administration, Topical; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000276:immunology / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006558:Herpes Genitalis / Q000188:drug therapy* / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D063065:Organophosphonates / Q000276:immunology / Q000494:pharmacology*; D000068698:Tenofovir; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014621:Vagina / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D014622:Vaginal Creams, Foams, and Jellies; D017201:Virus Shedding
chemical_list: D000890:Anti-Infective Agents; D000998:Antiviral Agents; D007376:Interleukin-2; D063065:Organophosphonates; D014409:Tumor Necrosis Factor-alpha; D014622:Vaginal Creams, Foams, and Jellies; D007371:Interferon-gamma; D000068698:Tenofovir; D000225:Adenine