%0 Journal Article %A Florian Hladik %A Adam Burgener %A Lamar Ballweber %A Raphael Gottardo %A Slim Fourati %A James Y. Dai %A Mark J. Cameron %A Lucia Vojtech %A Johanna Strobl %A Sean M. Hughes %A Craig Hoesley %A Philip Andrew %A Sherri Johnson %A Jeanna Piper %A David R. Friend %A T. Blake Ball %A Ross D. Cranston %A Kenneth H. Mayer %A M. Juliana McElrath %A Ian McGowan %T Mucosal effects of tenofovir 1% gel %D 2014 %R 10.1101/008607 %J bioRxiv %P 008607 %X BACKGROUND Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against sexual HIV transmission. Because this is a new prevention strategy targeting large numbers of healthy people, we broadly assessed its effects on the mucosa.METHODS AND FINDINGS In MTN-007, a phase 1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies taken at baseline, after one application or after seven daily applications (15 subjects/arm). Experiments were repeated using primary vaginal epithelial cells from four healthy women. After seven days of administration, tenofovir 1% gel had broad-ranging biological effects on the rectal mucosa, which were much more pronounced than—but different from—those caused by the detergent nonoxynol-9. Tenofovir profoundly suppressed anti-inflammatory mediators such as interleukin 10; increased T cell densities; caused mitochondrial dysfunction, possibly by blocking PNPT1 expression; and altered regulatory pathways of cell differentiation and survival. Except for leukocyte-derived factors, all these effects were replicated in primary vaginal epithelial cells, which also proliferated significantly faster in tenofovir's presence.CONCLUSIONS Tenofovir's suppression of anti-inflammatory activity could diminish its prophylactic efficacy over time. The breadth of mucosal changes, including mitochondrial dysfunction and epithelial proliferation, raises questions about its safety for long-term topical use. These findings suggest that a systems biology evaluation of mucosal effects may be beneficial before advancing to large-scale efficacy trials with topical HIV prevention agents that achieve high, long-lasting local drug concentrations. %U https://www.biorxiv.org/content/biorxiv/early/2014/09/01/008607.full.pdf