Cell Reports Medicine (Sep 2020)
Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection
- Sean M. Hughes,
- Claire N. Levy,
- Fernanda L. Calienes,
- Joanne D. Stekler,
- Urvashi Pandey,
- Lucia Vojtech,
- Alicia R. Berard,
- Kenzie Birse,
- Laura Noël-Romas,
- Brian Richardson,
- Jackelyn B. Golden,
- Michael Cartwright,
- Ann C. Collier,
- Claire E. Stevens,
- Marcel E. Curlin,
- Timothy H. Holtz,
- Nelly Mugo,
- Elizabeth Irungu,
- Elly Katabira,
- Timothy Muwonge,
- Javier R. Lama,
- Jared M. Baeten,
- Adam Burgener,
- Jairam R. Lingappa,
- M. Juliana McElrath,
- Romel Mackelprang,
- Ian McGowan,
- Ross D. Cranston,
- Mark J. Cameron,
- Florian Hladik
Affiliations
- Sean M. Hughes
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA
- Claire N. Levy
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA
- Fernanda L. Calienes
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Joanne D. Stekler
- Department of Epidemiology, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA
- Urvashi Pandey
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA
- Lucia Vojtech
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA
- Alicia R. Berard
- Departments of Obstetrics & Gynecology and Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada
- Kenzie Birse
- Departments of Obstetrics & Gynecology and Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada; Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH, USA
- Laura Noël-Romas
- Departments of Obstetrics & Gynecology and Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada; Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH, USA
- Brian Richardson
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
- Jackelyn B. Golden
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
- Michael Cartwright
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
- Ann C. Collier
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
- Claire E. Stevens
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
- Marcel E. Curlin
- Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA; Thailand Ministry of Public Health-US Centers for Disease Control and Prevention Collaboration, Nonthaburi, Thailand; Department of Medicine, Division of Infectious Diseases, Oregon Health and Sciences University, Portland, OR, USA
- Timothy H. Holtz
- Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA; Thailand Ministry of Public Health-US Centers for Disease Control and Prevention Collaboration, Nonthaburi, Thailand
- Nelly Mugo
- Partners in Health Research and Development, Kenya Medical Research Institute, Thika, Kenya; Center for Clinical Research (CCR), Kenya Medical Research Institute (KEMRI), Nairobi, Kenya; Department of Global Health, University of Washington, Seattle, WA, USA
- Elizabeth Irungu
- Partners in Health Research and Development, Kenya Medical Research Institute, Thika, Kenya
- Elly Katabira
- Infectious Disease Institute, Makerere University, Kampala, Uganda
- Timothy Muwonge
- Infectious Disease Institute, Makerere University, Kampala, Uganda
- Javier R. Lama
- Asociación Civil Impacta Salud y Educación, Lima, Peru
- Jared M. Baeten
- Department of Epidemiology, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA
- Adam Burgener
- Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH, USA; Departments of Obstetrics & Gynecology and Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada; Unit of Infectious Diseases, Department of Medicine Solna, Centre for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
- Jairam R. Lingappa
- Department of Pediatrics, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA
- M. Juliana McElrath
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA
- Romel Mackelprang
- Department of Global Health, University of Washington, Seattle, WA, USA
- Ian McGowan
- Orion Biotechnology, Ottawa, ON, Canada; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Ross D. Cranston
- Department of Infectious Diseases and Dermatology, University of Barcelona, Barcelona, Spain
- Mark J. Cameron
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
- Florian Hladik
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA; Corresponding author
- Journal volume & issue
-
Vol. 1,
no. 6
p. 100096
Abstract
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 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.
