Treatment with commonly used antiretroviral drugs induces a type I/III interferon signature in the gut in the absence of HIV infection

Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are used for HIV treatment and prevention. Previously, we found that topical rectal tenofovir gel caused immunological changes in the mucosa. Here we assessed the effect of oral TDF/FTC in three HIV pre-exposure prophylaxis trials, two with...

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Published inbioRxiv
Main Authors Hughes, Sean M, Levy, Claire N, Calienes, Fernanda, Stekler, Joanne D, Pandey, Urvashi, Vojtech, Lucia, Berard, Alicia R, Birse, Kenzie, Noel-Romas, Laura, Richardson, Brian, Golden, Jackelyn B, Cartwright, Michael, Collier, Ann C, Stevens, Claire E, Curlin, Marcel E, Holtz, Timothy H, Mugo, Nelly, Irungu, Elizabeth, Katabira, Elly, Muwonge, Timothy, Lama, Javier R, Baeten, Jared M, Burgener, Adam, Lingappa, Jairam R, Mcelrath, M Juliana, Mackelprang, Romel, Mcgowan, Ian, Cranston, Ross D, Cameron, Mark J, Hladik, Florian
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 03.08.2020
Subjects
Antiretroviral agents
Antiviral agents
Blood
Clinical trials
Disease transmission
DNA microarrays
Duodenum
Emtricitabine
Gastrointestinal tract
Gene expression
HIV
Human immunodeficiency virus
Immune response
Interferon
Mass spectroscopy
Oral administration
Prophylaxis
Rectum
Reproductive system
Ribonucleic acid
RNA
Tenofovir
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Summary:Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are used for HIV treatment and prevention. Previously, we found that topical rectal tenofovir gel caused immunological changes in the mucosa. Here we assessed the effect of oral TDF/FTC in three HIV pre-exposure prophylaxis trials, two with gastrointestinal and one with cervicovaginal biopsies. TDF/FTC induced type I/III interferon-related (IFN I/III) genes in the gastrointestinal tract, but not blood, with strong correlations between the two independent rectal biopsy groups (Spearman r=0.91) and between the rectum and duodenum (r=0.81). Gene set testing also indicated stimulation of type I/III pathways in the ectocervix, as well as of cellular proliferation in the duodenum. mRNA sequencing, digital droplet PCR, proteomics, and immunofluorescence staining confirmed IFN I/III pathway stimulation in the gastrointestinal tract. Thus, oral TDF/FTC stimulates an IFN-I/III signature throughout the gut, which could increase antiviral efficacy but also cause chronic immune activation in HIV prevention and treatment settings. Competing Interest Statement JMB is on advisory boards for Gilead Sciences, Merck and Janssen. IM is the Chief Medical Officer of Orion Biotechnology. All other authors report no conflicts. Footnotes * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139611 * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE138723 * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139655 * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139411 * https://doi.org/10.6084/m9.figshare.c.4704827
DOI:10.1101/701961