title: A topical microbicide gel formulation of CCR5 antagonist maraviroc prevents HIV-1 vaginal transmission in humanized RAG-hu mice.
abstract: For prevention of HIV infection many currently licensed anti-HIV drugs and new ones in the pipeline show potential as topically applied microbicides. While macaque models have been the gold standard for in vivo microbicide testing, they are expensive and sufficient numbers are not available. Therefore, a small animal model that facilitates rapid evaluation of potential candidates for their preliminary efficacy is urgently needed in the microbicide field. We previously demonstrated that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and that oral pre-exposure chemo-prophylactic strategies could be tested in this system. Here in these proof-of-concept studies, we extended this system for topical microbicide testing using HIV-1 as the challenge virus. Maraviroc, a clinically approved CCR5 inhibitor drug for HIV treatment, was formulated as a microbicide gel at 5 mM concentration in 2.2% hydroxyl ethyl cellulose. Female RAG-hu mice were challenged vaginally with HIV-1 an hour after intravaginal application of the maraviroc gel. Our results showed that maraviroc gel treated mice were fully protected against vaginal HIV-1 challenge in contrast to placebo gel treated mice which all became infected. These findings highlight the utility of the humanized mouse models for microbicide testing and, together with the recent data from macaque studies, suggest that maraviroc is a promising candidate for future microbicide clinical trials in the field.
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: C Preston
authors.initials: CP
authors.lastname: Neff
authors.forename: Theresa
authors.initials: T
authors.lastname: Kurisu
authors.forename: Thomas
authors.initials: T
authors.lastname: Ndolo
authors.forename: Kami
authors.initials: K
authors.lastname: Fox
authors.forename: Ramesh
authors.initials: R
authors.lastname: Akkina
mesh_terms: D000818:Animals; D000891:Anti-Infective Agents, Local / Q000737:chemistry / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D018791:CD4 Lymphocyte Count; D002626:Chemistry, Pharmaceutical; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005782:Gels; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000635:transmission*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D000077592:Maraviroc; D051379:Mice; D010919:Placebos; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D014621:Vagina / Q000187:drug effects / Q000821:virology*
chemical_list: D000891:Anti-Infective Agents, Local; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D004268:DNA-Binding Proteins; D005782:Gels; D018398:Homeodomain Proteins; D010919:Placebos; C499308:Rag2 protein, mouse; D014230:Triazoles; C064658:RAG-1 protein; D000077592:Maraviroc