title: Rectal transmission of transmitted/founder HIV-1 is efficiently prevented by topical 1% tenofovir in BLT humanized mice.
abstract: Rectal microbicides are being developed to prevent new HIV infections in both men and women. We focused our in vivo preclinical efficacy study on rectally-applied tenofovir. BLT humanized mice (n = 43) were rectally inoculated with either the primary isolate HIV-1JRCSF or the MSM-derived transmitted/founder (T/F) virus HIV-1THRO within 30 minutes following treatment with topical 1% tenofovir or vehicle. Under our experimental conditions, in the absence of drug treatment we observed 50% and 60% rectal transmission by HIV-1JRCSF and HIV-1THRO, respectively. Topical tenofovir reduced rectal transmission to 8% (1/12; log rank p = 0.03) for HIV-1JRCSF and 0% (0/6; log rank p = 0.02) for HIV-1THRO. This is the first demonstration that any human T/F HIV-1 rectally infects humanized mice and that transmission of the T/F virus can be efficiently blocked by rectally applied 1% tenofovir. These results obtained in BLT mice, along with recent ex vivo, Phase 1 trial and non-human primate reports, provide a critically important step forward in the development of tenofovir-based rectal microbicides.
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Center for AIDS Research University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Morgan L
authors.initials: ML
authors.lastname: Chateau
authors.forename: Paul W
authors.initials: PW
authors.lastname: Denton
authors.forename: Michael D
authors.initials: MD
authors.lastname: Swanson
authors.forename: Ian
authors.initials: I
authors.lastname: McGowan
authors.forename: J Victor
authors.initials: JV
authors.lastname: Garcia
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000285:Administration, Rectal; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018952:Antigens, CD34 / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission*; D015497:HIV-1 / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism / Q000637:transplantation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D063065:Organophosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D012007:Rectum / Q000821:virology*; D017422:Sequence Analysis, DNA; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D018952:Antigens, CD34; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine