title: Topical nonnucleoside reverse transcriptase inhibitor MC 1220 partially prevents vaginal RT-SHIV infection of macaques.
abstract: The availability of an effective vaginal microbicide would be a major step toward containment of HIV transmission as well as allowing women self-protection against HIV infection. Here we evaluated the efficacy of vaginal application of the potent nonnucleoside reverse transcriptase inhibitor (NNRTI) MC 1220 against vaginal challenge of macaques with RT-SHIV, a chimeric simian immunodeficiency virus (SIV) containing the reverse transcriptase (RT) gene of HIV-1. Challenge infection of monkeys with RT-SHIV currently represents the only nonhuman primate model available to test the anti-HIV-1 effects of NNRTIs. Two different gel formulations containing different MC 1220 concentrations were evaluated for efficacy in female rhesus macaques exposed to RT-SHIV. Five groups of five animals each were treated with two different gel compositions containing no drug, 0.1% or 0.5% MC 1220, followed by vaginal RT-SHIV challenge 30 min later. One animal in each group treated with the low concentration of MC 1220 as well as one control animal remained uninfected after vaginal challenge. By contrast, three of the animals receiving 0.5% MC 1220 remained uninfected, suggesting a threshold of the drug. Despite being negative for plasma viral RNA and absence of seroconversion, almost all uninfected animals exhibited SIV-specific T cells, either in the periphery or in lymph nodes draining the portal of virus entry. Our results make MC 1220 a promising compound for further development as a topical microbicide and warrant additional testing with improved formulation, long-lasting vaginal delivery systems, or even combinations with other inhibitors.
authors.affiliation: Unit "Infection Models," Deutsches Primatenzentrum GmbH, Goettingen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Stolte-Leeb
authors.forename: Roberta
authors.initials: R
authors.lastname: Loddo
authors.forename: Sophia
authors.initials: S
authors.lastname: Antimisiaris
authors.forename: Tina
authors.initials: T
authors.lastname: Schultheiss
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sauermann
authors.forename: Monika
authors.initials: M
authors.lastname: Franz
authors.forename: Spyridon
authors.initials: S
authors.lastname: Mourtas
authors.forename: Christophe
authors.initials: C
authors.lastname: Parsy
authors.forename: Richard
authors.initials: R
authors.lastname: Storer
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.forename: Christiane
authors.initials: C
authors.lastname: Stahl-Hennig
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage*; D018562:Disease Transmission, Infectious / Q000517:prevention & control*; D005260:Female; D005464:Fluorobenzenes; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics; D008253:Macaca mulatta; D011744:Pyrimidinones / Q000008:administration & dosage*; D011995:Recombination, Genetic; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control* / Q000635:transmission*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000235:genetics; D016896:Treatment Outcome
chemical_list: C506288:6-(1-(2,6-difluorophenyl)ethyl)-2-(dimethylamino)-5-methylpyrimidin-4(3H)-one; D000891:Anti-Infective Agents, Local; D005464:Fluorobenzenes; D011744:Pyrimidinones; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase