title: One percent tenofovir applied topically to humanized BLT mice and used according to the CAPRISA 004 experimental design demonstrates partial protection from vaginal HIV infection, validating the BLT model for evaluation of new microbicide candidates.
abstract: Recent iPrEx clinical trial results provided evidence that systemic preexposure prophylaxis (PrEP) with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) can partially prevent rectal HIV transmission in humans. Similarly, we have previously demonstrated that systemic administration of the same FTC-TDF combination efficiently prevented rectal transmission in humanized bone marrow/liver/thymus (BLT) mice. The CAPRISA 004 trial recently demonstrated that topical application of the tenofovir could partially prevent vaginal HIV-1 transmission in humans. To further validate the usefulness of the BLT mouse model for testing HIV prevention strategies, we evaluated the topical administration of tenofovir as used in CAPRISA 004 to prevent vaginal HIV transmission in BLT mice. Our results demonstrate that vaginally administered 1% tenofovir significantly reduced HIV transmission in BLT mice (P = 0.002). Together with the results obtained after systemic antiretroviral PrEP, these topical inhibitor data serve to validate the use of humanized BLT mice to evaluate both systemic and topical inhibitors of HIV transmission. Based on these observations, we tested six additional microbicide candidates for their ability to prevent vaginal HIV transmission: a C-peptide fusion inhibitor (C52L), a membrane-disrupting amphipathic peptide inhibitor (C5A), a trimeric d-peptide fusion inhibitor (PIE12-Trimer), a combination of reverse transcriptase inhibitors (FTC-TDF), a thioester zinc finger inhibitor (TC247), and a small-molecule Rac inhibitor (NSC23766). No protection was seen with the Rac inhibitor NSC23766. The thioester compound TC247 offered partial protection. Significant protection was afforded by FTC-TDF, and complete protection was offered by three different peptide inhibitors tested. Our results demonstrate that these effective topical inhibitors have excellent potential to prevent vaginal HIV transmission in humans.
authors: Division of Infectious Diseases, Department of Internal Medicine, Center for AIDS Research, University of North Carolina, Chapel Hill, North Carolina 27510, USA.
authors: Paul W
authors: PW
authors: Denton
authors: Florence
authors: F
authors: Othieno
authors: Francisco
authors: F
authors: Martinez-Torres
authors: Wei
authors: W
authors: Zou
authors: John F
authors: JF
authors: Krisko
authors: Elisa
authors: E
authors: Fleming
authors: Sima
authors: S
authors: Zein
authors: Daniel A
authors: DA
authors: Powell
authors: Angela
authors: A
authors: Wahl
authors: Youn Tae
authors: YT
authors: Kwak
authors: Brett D
authors: BD
authors: Welch
authors: Michael S
authors: MS
authors: Kay
authors: Deborah A
authors: DA
authors: Payne
authors: Philippe
authors: P
authors: Gallay
authors: Ettore
authors: E
authors: Appella
authors: Jacob D
authors: JD
authors: Estes
authors: Min
authors: M
authors: Lu
authors: J Victor
authors: JV
authors: Garcia
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