title: Evaluation of -2 RANTES vaginal microbicide formulations in a nonhuman primate simian/human immunodeficiency virus (SHIV) challenge model.
abstract: A potential strategy to combat the worldwide AIDS epidemic is to develop a vaginal microbicide that prevents the sexual transmission of HIV-1. One approach for preventing vaginal HIV transmission is to block the viral coreceptor CCR5 with naturally occurring chemokine ligands. In this study, we used a cynomolgus macaque model to evaluate whether a variant of the CCR5 ligand RANTES (-2 RANTES), tested alone or in a nonphospholipid liposome carrier (Novasomes 7474), blocks vaginal challenge with a CCR5-tropic simian/human immunodeficiency virus (SHIV(162P3)). When tested in vitro, the synthetic chemokine potently inhibited SHIV(162P3) infection of cynomolgus macaque peripheral blood mononuclear cells (PBMC). Colposcopic examinations of treated animals and histological examination of cervicovaginal biopsies showed minimal signs of tissue inflammation following vaginal application of Novasomes 7474, -2 RANTES formulated in Novasomes 7474, or -2 RANTES alone. Following vaginal challenge with SHIV(162P3), complete protection was observed in four of six animals treated vaginally with -2 RANTES (0.13 mM) formulated in Novasomes 7474. However, the same proportion of animals was protected by treatment with Novasomes 7474 carrier alone. Two of five animals treated with 0.5 mM -2 RANTES in PBS were protected from infection. Further, all animals were infected when treated with lower chemokine concentrations. These findings indicate that natural CCR5 ligands may have limited efficacy in stringent nonhuman primate models for vaginal infection. In comparison, liposomal agents such as Novasomes 7474 provide comparatively robust protection against vaginal transmission.
authors.affiliation: Division of Basic Science, Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, MD 21201, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Kish-Catalone
authors.forename: Ranajit
authors.initials: R
authors.lastname: Pal
authors.forename: John
authors.initials: J
authors.lastname: Parrish
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rose
authors.forename: Lindsey
authors.initials: L
authors.lastname: Hocker
authors.forename: Lauren
authors.initials: L
authors.lastname: Hudacik
authors.forename: Marvin
authors.initials: M
authors.lastname: Reitz
authors.forename: Robert
authors.initials: R
authors.lastname: Gallo
authors.forename: Anthony
authors.initials: A
authors.lastname: Devico
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000891:Anti-Infective Agents, Local / Q000494:pharmacology* / Q000633:toxicity; D018946:Chemokine CCL5 / Q000494:pharmacology*; D003127:Colposcopy; D004195:Disease Models, Animal; D005069:Evaluation Studies as Topic; D005260:Female; D015497:HIV-1 / Q000187:drug effects*; D008081:Liposomes; D008253:Macaca mulatta; D012367:RNA, Viral / Q000097:blood; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control*; D013997:Time Factors; D014621:Vagina / Q000187:drug effects; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D000891:Anti-Infective Agents, Local; D018946:Chemokine CCL5; D008081:Liposomes; D012367:RNA, Viral