title: Oral pre-exposure prophylaxis by anti-retrovirals raltegravir and maraviroc protects against HIV-1 vaginal transmission in a humanized mouse model.
abstract: Sexual HIV-1 transmission by vaginal route is the most predominant mode of viral transmission, resulting in millions of new infections every year. In the absence of an effective vaccine, there is an urgent need to develop other alternative methods of pre-exposure prophylaxis (PrEP). Many novel drugs that are currently approved for clinical use also show great potential to prevent viral sexual transmission when administered systemically. A small animal model that permits rapid preclinical evaluation of potential candidates for their systemic PrEP efficacy will greatly enhance progress in this area of investigation. We have previously shown that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and displays CD4 T cell loss typical to that seen in the human. Thus far systemic PrEP studies have been primarily limited to RT inhibitors exemplified by tenofovir and emtricitabine. In these proof-of-concept studies we evaluated two new classes of clinically approved drugs with different modes of action namely, an integrase inhibitor raltegravir and a CCR5 inhibitor maraviroc as potential systemically administered chemo-prophylactics. Our results showed that oral administration of either of these drugs fully protects against vaginal HIV-1 challenge in the RAG-hu mouse model. Based on these results both these drugs show great promise for further development as orally administered PrEPs.
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: Thomas
authors.initials: T
authors.lastname: Ndolo
authors.forename: Apurva
authors.initials: A
authors.lastname: Tandon
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Habu
authors.forename: Ramesh
authors.initials: R
authors.lastname: Akkina
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D003510:Cyclohexanes / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D000077592:Maraviroc; D051379:Mice; D008822:Mice, Transgenic; D056990:Post-Exposure Prophylaxis / Q000379:methods*; D011760:Pyrrolidinones / Q000627:therapeutic use*; D000068898:Raltegravir Potassium; D014230:Triazoles / Q000627:therapeutic use*; D014621:Vagina / Q000821:virology
chemical_list: D019380:Anti-HIV Agents; D003510:Cyclohexanes; D011760:Pyrrolidinones; D014230:Triazoles; D000068898:Raltegravir Potassium; D000077592:Maraviroc