Mucosal effects of tenofovir 1% gel
- University of Washington, United States
- Fred Hutchinson Cancer Research Center, United States
- University of Manitoba, Canada
- Public Health Agency of Canada, Canada
- Vaccine and Gene Therapy Institute of Florida, United States
- University of Alabama, United States
- FHI 360, United States
- National Institutes of Health, United States
- Eastern Virginia Medical School, United States
- University of Pittsburgh School of Medicine, United States
- Magee-Women's Research Institute, United States
- Beth Israel Deaconess Hospital, Harvard Medical School, United States
Figures
Figure 1 with 2 supplements
Tenofovir-induced gene expression changes in the human rectum.
(A) Heat map of differentially expressed genes in eight participants after a single (I) and after seven consecutive once-daily (VII) rectal applications of tenofovir 1% gel compared to baseline in …
Figure 1—figure supplement 1
Correlation of log2 fold gene induction by tenofovir 1% gel from baseline to Day VII between 9 and 15 cm biopsies.
All 137 genes at 9 cm significantly induced (FDR < 0.05) and with log2 fold change > 0.5 are included. Genes depicted as blue dots were significantly induced in both 9 and 15 cm biopsies (15 cm FDR <…
Figure 1—figure supplement 2
Log2 fold gene suppression (A) and induction (B) from baseline to Day VII caused by N-9 and tenofovir in 9 cm biopsies.
(A) All genes with an estimated FDR ≤ 0.05 and a log2 fold expression change of ≤ 0.5 are included (N-9: 56 genes; tenofovir: 505 genes). (B) All genes with an estimated FDR ≤ 0.05 and a log2 fold …
Figure 2 with 2 supplements
Confirmation of microarray data.
(A and B) Quantification of mRNA copy numbers measured in 9 cm biopsies by reverse transcription (RT) droplet digital PCR (ddPCR) relative to the housekeeping gene hemoglobin beta (HBB) copy numbers …
Figure 2—figure supplement 1
Immunohistochemistry for CD7, and immunofluorescence for CD3, in rectal biopsies before (0) and after 7 days (VII) of daily tenofovir 1% gel use.
Individual study participants are designated by letters. Blue indicates nuclei, red indicates CD3 or CD7.
Figure 2—figure supplement 2
Immunohistochemistry for IL-10 and ubiquitin D (UBD) in rectal biopsies before (0) and after 7 days (VII) of daily tenofovir 1% gel use.
Individual study participants are designated by letters. Blue indicates nuclei, brown indicates IL-10 or UBD.
Figure 3 with 2 supplements
Expression pattern and functional pathway analysis.
(A) Ingenuity pathways analysis of tenofovir-induced effects in rectal biopsies, showing cellular localizations of and relationships between individual gene products. Red symbols indicate induction …
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Figure 3—source data 1
Pearson correlation coefficients of pre-processed microarray probe expression values between the three primary vaginal cell cultures.
- https://doi.org/10.7554/eLife.04525.010
Figure 3—figure supplement 1
Average strength of gene induction by tenofovir 1% gel across all 8 microarray study participants.
Heat map colors depict fold-change at Day I and Day VII over baseline. Baseline is depicted as the vertical bar labeled ‘0’ filled with the shade of blue corresponding to a fold-change of 1. Genes …
Figure 3—figure supplement 2
Selected biological processes defined in the InnateDB database with significant enrichment of genes suppressed or induced by tenofovir 1% gel at Day VII in 9 cm biopsies.
Green bars depict the percentage of genes identified as suppressed in a particular process out of the total number of genes included by InnateDB in that process. Red bars depict corresponding …
Figure 4
Effects of tenofovir on primary vaginal epithelial cells.
(A) Number of suppressed (green) and induced (red) genes in response to treatment with 50 μM (open circles) or 500 μM (filled circles) tenofovir for 1, 4, 7, or 14 days (n = 3 cell lines from …
Figure 5
Quantification of mitochondria-associated parameters.
(A) PNPT1 mRNA copy numbers measured in 9 and 15 cm biopsies at baseline (0), after a single tenofovir gel application (I) and after seven consecutive once-daily applications (VII) by RT-ddPCR …
Figure 6
Unbiased mass spectrometry proteomics in rectal secretions from five study participants each in the tenofovir and the no treatment arm.
(A) 483 proteins were consistently detected in all 10 study participants. Of these, 382 proteins in the tenofovir arm had log2 values > 0 for fold change between baseline and after seven daily gel …
Additional files
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Supplementary file 1
Summary of effect sizes and statistical significance testing.
- https://doi.org/10.7554/eLife.04525.016
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Supplementary file 2
Lists of genes significantly up- or down-regulated by tenofovir 1% or nonoxynol-9 2% gels in 9 cm rectal biopsies over 7 days of treatment.
- https://doi.org/10.7554/eLife.04525.017
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Reporting standard 1
CONSORT checklist.
- https://doi.org/10.7554/eLife.04525.020
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Reporting standard 2
CONSORT flow chart.
- https://doi.org/10.7554/eLife.04525.021
