Rectal 1% Tenofovir Gel Use Associates with Altered Epidermal Protein Expression.
Rectal use of a 1% tenofovir (TFV) gel is currently being evaluated for HIV prevention. While careful assessment of mucosal safety of candidate microbicides is a primary concern, tools to assess mucosal toxicity are limited. Mass spectrometry-based proteomics is a sensitive and high-throughput technique that can provide in-depth information on inflammation processes in biological systems. In this study, we utilized a proteomics approach to characterize mucosal responses in study participants involved in a phase 1 clinical trial of a rectal TFV-based gel. Project Gel was a phase 1 randomized (1:1), double-blind, multisite, placebo-controlled trial in which 24 participants received rectal TFV or a universal placebo [hydroxyethyl cellulose (HEC)] over a course of 8 daily doses. Rectal mucosal swabs were collected after 0, 1, and 8 doses and were analyzed by label-free tandem mass spectrometry. Differential protein expression was evaluated using a combination of paired (time-effects) and unpaired (across study arm) t-tests, and multivariate [least absolute shrinkage and selection operator (LASSO)] modeling. Within the TFV arm, 7% (17/249, p < .05) and 10% (25/249, p < .05) of total proteins changed after 1 and 8 daily applications of TFV gel, respectively, compared to 3% (7/249, p < .05) and 6% (16/249, p < .05) in the HEC arm. Biofunctional analysis associated TFV use with a decrease in epidermal barrier proteins (adj. p = 1.21 × 10-10). Multivariate modeling identified 13 proteins that confidently separated TFV gel users (100% calibration and 96% cross-validation accuracy), including the epithelial integrity factors (FLMNB, CRNN, CALM), serpins (SPB13, SPB5), and cytoskeletal proteins (VILI, VIME, WRD1). This study suggested that daily rectal applications of a 1% TFV gel may be associated with mucosal proteome changes involving epidermal development. Further assessment of more extended use of TFV-gel is recommended to validate these initial associations.
1 National HIV and Retrovirology Laboratory, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada , Winnipeg, Canada .|2 Medical Microbiology and Infectious Diseases, University of Manitoba , Winnipeg, Canada .
Laura
L
Romas
1 National HIV and Retrovirology Laboratory, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada , Winnipeg, Canada .|2 Medical Microbiology and Infectious Diseases, University of Manitoba , Winnipeg, Canada .
Kenzie
K
Birse
3 Fenway Health and Harvard Medical School , Boston, Massachusetts.
Kenneth H
KH
Mayer
1 National HIV and Retrovirology Laboratory, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada , Winnipeg, Canada .
Max
M
Abou
4 Mass Spectrometry and Proteomics Core Facility, National Microbiology Laboratory, Public Health Agency of Canada , Winnipeg, Canada .
Garrett
G
Westmacott
5 HIV Center for Clinical and Behavioral Studies, Columbia University , New York, New York.
Rebecca
R
Giguere
6 University of Puerto Rico , San Juan, Puerto Rico .
Irma
I
Febo
7 Department of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
Ross D
RD
Cranston
5 HIV Center for Clinical and Behavioral Studies, Columbia University , New York, New York.
Alex
A
Carballo-Diéguez
7 Department of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
Ian
I
McGowan
1 National HIV and Retrovirology Laboratory, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada , Winnipeg, Canada .|2 Medical Microbiology and Infectious Diseases, University of Manitoba , Winnipeg, Canada .|8 Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet , Stockholm, Sweden .
Adam
A
Burgener
D000285:Administration, Rectal; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D004311:Double-Blind Method; D005260:Female; D005782:Gels / Q000008:administration & dosage*; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects*; D008297:Male; D010919:Placebos / Q000008:administration & dosage; D011506:Proteins / Q000032:analysis*; D040901:Proteomics; D053719:Tandem Mass Spectrometry; D000068698:Tenofovir / Q000008:administration & dosage*
D019380:Anti-HIV Agents; D005782:Gels; D010919:Placebos; D011506:Proteins; D000068698:Tenofovir
innate immunity; microbicides; mucosal immunology; proteomics; rectal; systems biology