RT Journal Article
SR Electronic
T1 Mucosal effects of tenofovir 1% gel
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 008607
DO 10.1101/008607
A1 Florian Hladik
A1 Adam Burgener
A1 Lamar Ballweber
A1 Raphael Gottardo
A1 Slim Fourati
A1 James Y. Dai
A1 Mark J. Cameron
A1 Lucia Vojtech
A1 Johanna Strobl
A1 Sean M. Hughes
A1 Craig Hoesley
A1 Philip Andrew
A1 Sherri Johnson
A1 Jeanna Piper
A1 David R. Friend
A1 T. Blake Ball
A1 Ross D. Cranston
A1 Kenneth H. Mayer
A1 M. Juliana McElrath
A1 Ian McGowan
YR 2014
UL http://biorxiv.org/content/early/2014/09/01/008607.abstract
AB 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.