title: Efficacy of topical tenofovir against transmission of a tenofovir-resistant SHIV in macaques.
abstract: BACKGROUND
  Topically delivered tenofovir (TFV) from intravaginal rings, tablets, or gels is being evaluated for HIV prevention. We previously demonstrated that TFV delivered vaginally by gel protected macaques from vaginal infection with SHIV. Here we investigated efficacy of the TFV gel against vaginal transmission of a TFV-resistant SHIV containing the K65R mutation (SHIV162P3K65R) and its relationship to drug levels in vaginal tissues.
  
  
  RESULTS
  SHIV162P3K65R shows approximately a 5-fold reduction in susceptibility to TFV compared to wild-type SHIV. Efficacy was evaluated in pig-tailed macaques exposed vaginally twice-weekly (up to 10 weeks) to SHIV162P3K65R 30 min after receiving placebo (n = 6) or 1% TFV (n = 6) gel. Four of the six controls were infected after a median of 5 exposures. In contrast, five of six macaques that received TFV gel remained uninfected after 20 vaginal SHIV162P3K65R exposures, resulting in an estimated efficacy of 75%. The mean intracellular TFV-diphosphate (TFV-DP) concentrations in vaginal lymphocytes 4 h after a single gel dose were found to be high (1,631 fmol/10(6) cells, range 492-3,847) and within the in vitro IC75 range (1,206 fmol/10(6) cells) for SHIV162P3K65R.
  
  
  CONCLUSIONS
  Both the modest resistance conferred by K65R and the high TFV-DP exposure in vaginal lymphocytes, likely explain the observed protection. The findings in this model do not predict complete loss of protection by topical TFV against vaginal exposure to HIV-1K65R viruses and provide a tissue drug target for high efficacy. These data will facilitate the development of TFV delivery platforms that have high activity on both wild-type and TFV-resistant viruses.
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, MS G45, 1600 Clifton Road, Atlanta, GA, 30329, USA. cdobard@cdc.gov.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Dobard
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, MS G45, 1600 Clifton Road, Atlanta, GA, 30329, USA. fys6@cdc.gov.
authors.forename: Sunita
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, MS G45, 1600 Clifton Road, Atlanta, GA, 30329, USA. myc8@cdc.gov.
authors.forename: Mian-Er
authors.initials: ME
authors.lastname: Cong
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, MS G45, 1600 Clifton Road, Atlanta, GA, 30329, USA. wgr2@cdc.gov.
authors.forename: Rolieria
authors.initials: R
authors.lastname: West
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, MS G45, 1600 Clifton Road, Atlanta, GA, 30329, USA. wcn5@cdc.gov.
authors.forename: Natalia
authors.initials: N
authors.lastname: Makarova
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, MS G45, 1600 Clifton Road, Atlanta, GA, 30329, USA. fka5@cdc.gov.
authors.forename: Angela
authors.initials: A
authors.lastname: Holder
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, MS G45, 1600 Clifton Road, Atlanta, GA, 30329, USA. chp3@cdc.gov.
authors.forename: Chou-Pong
authors.initials: CP
authors.lastname: Pau
authors.affiliation: Quantitative Sciences and Data Management Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA. dlh4@cdc.gov.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Hanson
authors.affiliation: Yerkes Primate Center, Emory University, Atlanta, GA, USA. FNOVEMBRE@sw.org.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Novembre
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, MS G45, 1600 Clifton Road, Atlanta, GA, 30329, USA. jng5@cdc.gov.
authors.forename: Jose Gerardo
authors.initials: JG
authors.lastname: Garcia-Lerma
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, MS G45, 1600 Clifton Road, Atlanta, GA, 30329, USA. wmh2@cdc.gov.
authors.forename: Walid
authors.initials: W
authors.lastname: Heneine
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D005260:Female; D005782:Gels; D006678:HIV / Q000187:drug effects*; D015658:HIV Infections / Q000821:virology; D006801:Humans; D008255:Macaca radiata; D065129:Pre-Exposure Prophylaxis; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control / Q000635:transmission* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000235:genetics; D000068698:Tenofovir / Q000008:administration & dosage*; D014621:Vagina / Q000187:drug effects* / Q000821:virology
chemical_list: D005782:Gels; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir