Efficacy of topical tenofovir against transmission of a tenofovir-resistant SHIV in macaques

Retrovirology

Walid Heneine¹  Jose Gerardo Garcia-Lerma¹  Francis J Novembre²  Debra L. Hanson³  Chou-Pong Pau¹  Angela Holder¹  Natalia Makarova¹  Rolieria West¹  Mian-er Cong¹  Sunita Sharma¹  Charles W Dobard¹ 

[1] Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, MS G45, 1600 Clifton Road, Atlanta 30329, GA, USA;Yerkes Primate Center, Emory University, Atlanta, GA, USA;Quantitative Sciences and Data Management Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA

关键词: Microbicides;    Tenofovir;    HIV-1 drug resistance;    Pre-exposure prophylaxis;   

Others  :  1223837
DOI  :  10.1186/s12977-015-0195-z

 received in 2015-06-01, accepted in 2015-07-24,  发布年份 2015

【 摘 要 】

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 (SHIV162P3 _K65R ) and its relationship to drug levels in vaginal tissues.

Results

SHIV162P3 _K65Rshows 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 SHIV162P3 _K65R30 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 SHIV162P3 _K65Rexposures, 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 ⁶cells, range 492–3,847) and within the in vitro IC ₇₅range (1,206 fmol/10 ⁶cells) for SHIV162P3 _K65R .

Conclusion

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-1 _K65Rviruses 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.

【 授权许可】

   
2015 Dobard et al.

【 图 表 】

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