PMID- 21593172
OWN - NLM
STAT- MEDLINE
DCOM- 20110921
LR  - 20220316
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 85
IP  - 15
DP  - 2011 Aug
TI  - 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.
PG  - 7582-93
LID - 10.1128/JVI.00537-11 [doi]
AB  - 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.
FAU - Denton, Paul W
AU  - Denton PW
AD  - Division of Infectious Diseases, Department of Internal Medicine, Center for AIDS 
      Research, University of North Carolina, Chapel Hill, North Carolina 27510, USA.
FAU - Othieno, Florence
AU  - Othieno F
FAU - Martinez-Torres, Francisco
AU  - Martinez-Torres F
FAU - Zou, Wei
AU  - Zou W
FAU - Krisko, John F
AU  - Krisko JF
FAU - Fleming, Elisa
AU  - Fleming E
FAU - Zein, Sima
AU  - Zein S
FAU - Powell, Daniel A
AU  - Powell DA
FAU - Wahl, Angela
AU  - Wahl A
FAU - Kwak, Youn Tae
AU  - Kwak YT
FAU - Welch, Brett D
AU  - Welch BD
FAU - Kay, Michael S
AU  - Kay MS
FAU - Payne, Deborah A
AU  - Payne DA
FAU - Gallay, Philippe
AU  - Gallay P
FAU - Appella, Ettore
AU  - Appella E
FAU - Estes, Jacob D
AU  - Estes JD
FAU - Lu, Min
AU  - Lu M
FAU - Garcia, J Victor
AU  - Garcia JV
LA  - eng
GR  - U19 AI082637/AI/NIAID NIH HHS/United States
GR  - R01 AI073146/AI/NIAID NIH HHS/United States
GR  - R01 AI087470/AI/NIAID NIH HHS/United States
GR  - R56 AI076168/AI/NIAID NIH HHS/United States
GR  - 266200400088C/PHS HHS/United States
GR  - AI078791/AI/NIAID NIH HHS/United States
GR  - R21 AI078791/AI/NIAID NIH HHS/United States
GR  - R01 AI076168/AI/NIAID NIH HHS/United States
GR  - AI071940/AI/NIAID NIH HHS/United States
GR  - AI079782/AI/NIAID NIH HHS/United States
GR  - R21 AI079782/AI/NIAID NIH HHS/United States
GR  - AI073146/AI/NIAID NIH HHS/United States
GR  - P30 AI050410/AI/NIAID NIH HHS/United States
GR  - T32 AI005284/AI/NIAID NIH HHS/United States
GR  - R21 AI071940/AI/NIAID NIH HHS/United States
GR  - R33 AI079782/AI/NIAID NIH HHS/United States
GR  - R01 AI068591/AI/NIAID NIH HHS/United States
GR  - AI082637/AI/NIAID NIH HHS/United States
GR  - 5T32AI005284/AI/NIAID NIH HHS/United States
GR  - R33 AI071940/AI/NIAID NIH HHS/United States
GR  - P30 AI50410/AI/NIAID NIH HHS/United States
GR  - AI076168/AI/NIAID NIH HHS/United States
GR  - AI68591/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Validation Study
DEP - 20110518
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (DNA Primers)
RN  - 0 (Organophosphonates)
RN  - 0 (Receptors, CCR5)
RN  - 0 (Reverse Transcriptase Inhibitors)
RN  - 99YXE507IL (Tenofovir)
RN  - JAC85A2161 (Adenine)
SB  - IM
MH  - Adenine/administration & dosage/*analogs & derivatives
MH  - Administration, Topical
MH  - Animals
MH  - Base Sequence
MH  - CD4-Positive T-Lymphocytes/immunology
MH  - Chimera
MH  - DNA Primers
MH  - *Disease Models, Animal
MH  - Drug Evaluation, Preclinical
MH  - Female
MH  - HIV Infections/immunology/*prevention & control/transmission
MH  - Humans
MH  - Mice
MH  - Organophosphonates/*administration & dosage
MH  - Receptors, CCR5/immunology
MH  - Reverse Transcriptase Inhibitors/*administration & dosage
MH  - Tenofovir
MH  - *Vagina
PMC - PMC3147928
EDAT- 2011/05/20 06:00
MHDA- 2011/09/22 06:00
PMCR- 2012/02/01
CRDT- 2011/05/20 06:00
PHST- 2011/05/20 06:00 [entrez]
PHST- 2011/05/20 06:00 [pubmed]
PHST- 2011/09/22 06:00 [medline]
PHST- 2012/02/01 00:00 [pmc-release]
AID - JVI.00537-11 [pii]
AID - 0537-11 [pii]
AID - 10.1128/JVI.00537-11 [doi]
PST - ppublish
SO  - J Virol. 2011 Aug;85(15):7582-93. doi: 10.1128/JVI.00537-11. Epub 2011 May 18.