@article{27a7596832a9474eb7aff4b9e9f5a01c,
title = "Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection",
abstract = "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 assess the effect of oral TDF/FTC in three HIV pre-exposure prophylaxis trials, two with gastrointestinal and one with cervicovaginal biopsies. TDF/FTC induces 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 indicates stimulation of the type I/III pathways in the ectocervix and of cellular proliferation in the duodenum. mRNA sequencing, digital droplet PCR, proteomics, and immunofluorescence confirm 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.",
keywords = "ART, HIV, HIV cure, ISG15, antiretroviral treatment, chronic immune activation, gut, interferon, tenofovir",
author = "Hughes, {Sean M.} and Levy, {Claire N.} and Calienes, {Fernanda L.} and Stekler, {Joanne D.} and Urvashi Pandey and Lucia Vojtech and Berard, {Alicia R.} and Kenzie Birse and Laura No{\"e}l-Romas and Brian Richardson and Golden, {Jackelyn B.} and Michael Cartwright and Collier, {Ann C.} and Stevens, {Claire E.} and Curlin, {Marcel E.} and Holtz, {Timothy H.} and Nelly Mugo and Elizabeth Irungu and Elly Katabira and Timothy Muwonge and Lama, {Javier R.} and Baeten, {Jared M.} and Adam Burgener and Lingappa, {Jairam R.} and McElrath, {M. Juliana} and Romel Mackelprang and Ian McGowan and Cranston, {Ross D.} and Cameron, {Mark J.} and Florian Hladik",
note = "Funding Information: We wish to express gratitude to all of the study volunteers for their participation. We are grateful to Max Abou and Lauren Girard for proteomic wet lab support as well as Stuart McCorrister and Garrett Westmacott for mass spectrometry technical support. We acknowledge the Fred Hutchinson Experimental Histopathology (Sunni Farley, Savanh Chanthaphavong, and Li-Ya Huang) and Genomics (Cassie Sather and Crissa Bennett) core facilities for their assistance. This work was funded by NIH R01AI116292 (to F.H.), NIH R01AI111738 (to J.R. Lingappa), the Bill and Melinda Gates Foundation grant no. 47674 (to J.M.B.), NIH R01AI134293 (to R.M.), NIH AI027757 (to J.M.B.), NIH AI069481 (to A.C.C. and M.J.M.). M.J.C. and I.M. were supported by the Microbicide Trials Network ( UM1AI068633 , Sharon Hillier, principal investigator). A.B. was supported by the Canadian Institutes of Health Research ( 154042 ) and NIH ( R01DK112254 ). This work was also supported by the Emory-Centers for Disease Control and Prevention (CDC) HIV/AIDS Clinical Trials Unit Grant award no. UM1AI069418 from the NIH ( National Institute of Allergy and Infectious Diseases [NIAID]).The ddPCR portion of this work was supported by a grant from the James B. Pendleton Charitable Trust . The National Cancer Institute (NCI) 5 P30 CA015704-44 Cancer Center Support Grant supported the Fred Hutchinson Experimental Histopathology core facility. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the funding agencies or the CDC. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The corresponding author had full access to all of the data in the study and had the final responsibility for the decision to submit for publication. Funding Information: We wish to express gratitude to all of the study volunteers for their participation. We are grateful to Max Abou and Lauren Girard for proteomic wet lab support as well as Stuart McCorrister and Garrett Westmacott for mass spectrometry technical support. We acknowledge the Fred Hutchinson Experimental Histopathology (Sunni Farley, Savanh Chanthaphavong, and Li-Ya Huang) and Genomics (Cassie Sather and Crissa Bennett) core facilities for their assistance. This work was funded by NIH R01AI116292 (to F.H.), NIH R01AI111738 (to J.R. Lingappa), the Bill and Melinda Gates Foundation grant no. 47674 (to J.M.B.), NIH R01AI134293 (to R.M.), NIH AI027757 (to J.M.B.), NIH AI069481 (to A.C.C. and M.J.M.). M.J.C. and I.M. were supported by the Microbicide Trials Network (UM1AI068633, Sharon Hillier, principal investigator). A.B. was supported by the Canadian Institutes of Health Research (154042) and NIH (R01DK112254). This work was also supported by the Emory-Centers for Disease Control and Prevention (CDC) HIV/AIDS Clinical Trials Unit Grant award no. UM1AI069418 from the NIH (National Institute of Allergy and Infectious Diseases [NIAID]).The ddPCR portion of this work was supported by a grant from the James B. Pendleton Charitable Trust. The National Cancer Institute (NCI) 5 P30 CA015704-44 Cancer Center Support Grant supported the Fred Hutchinson Experimental Histopathology core facility. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the funding agencies or the CDC. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The corresponding author had full access to all of the data in the study and had the final responsibility for the decision to submit for publication. Data Curation, S.M.H. C.N.L. A.R.B. K.B. L.N.R. B.R. J.B.G. and M.C.; Formal Analysis, S.M.H. and C.N.L.; Funding Acquisition, J.M.B. J.R. Lingappa, I.M. R.D.C. and F.H.; Investigation, S.M.H. C.N.L. F.L.C. U.P. A.R.B. K.B. L.N.-R. B.R. J.B.G. and M.C.; Methodology, S.M.H. U.P. and F.H.; Project Administration, S.M.H. and F.H.; Resources, F.L.C. J.D.S. A.C.C. C.E.S. M.E.C. T.H.H. N.M. E.I. E.K. T.M. J.R. Lama, J.M.B. J.R. Lingappa, R.M. I.M. and R.D.C.; Software, S.M.H. and C.N.L.; Supervision, J.M.B. A.B. J.R. Lingappa, M.J.M. M.J.C. and F.H.; Visualization, S.M.H.; Writing ? Original Draft, S.M.H. and F.H.; Writing ? Review & Editing, S.M.H. C.N.L. J.D.S. L.V. B.R. J.B.G. A.C.C. M.E.C. T.H.H. J.M.B. J.R. Lingappa, I.M. R.D.C. M.J.C. and F.H. J.M.B. is on the advisory boards of Gilead Sciences, Merck, and Janssen. I.M. is the Chief Medical Officer of Orion Biotechnology. All of the other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = sep,
day = "22",
doi = "10.1016/j.xcrm.2020.100096",
language = "English (US)",
volume = "1",
journal = "Cell Reports Medicine",
issn = "2666-3791",
publisher = "Cell Press",
number = "6",
}