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

doi:10.1016/j.xcrm.2020.100096

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 MuwongeJavier 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

Infectious Diseases

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	English (US)
Article number	100096
Journal	Cell Reports Medicine
Volume	1
Issue number	6
DOIs	https://doi.org/10.1016/j.xcrm.2020.100096
State	Published - Sep 22 2020

Keywords

ART
HIV
HIV cure
ISG15
antiretroviral treatment
chronic immune activation
gut
interferon
tenofovir

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.xcrm.2020.100096

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Hughes, S. M., Levy, C. N., Calienes, F. L., Stekler, J. D., Pandey, U., Vojtech, L., Berard, A. R., Birse, K., Noël-Romas, L., Richardson, B., Golden, J. B., Cartwright, M., Collier, A. C., Stevens, C. E., Curlin, M. E., Holtz, T. H., Mugo, N., Irungu, E., Katabira, E., ... Hladik, F. (2020). Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection. Cell Reports Medicine, 1(6), Article 100096. https://doi.org/10.1016/j.xcrm.2020.100096

Hughes, SM, Levy, CN, Calienes, FL, Stekler, JD, Pandey, U, Vojtech, L, Berard, AR, Birse, K, Noël-Romas, L, Richardson, B, Golden, JB, Cartwright, M, Collier, AC, Stevens, CE, Curlin, ME, Holtz, TH, Mugo, N, Irungu, E, Katabira, E, Muwonge, T, Lama, JR, Baeten, JM, Burgener, A, Lingappa, JR, McElrath, MJ, Mackelprang, R, McGowan, I, Cranston, RD, Cameron, MJ & Hladik, F 2020, 'Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection', Cell Reports Medicine, vol. 1, no. 6, 100096. https://doi.org/10.1016/j.xcrm.2020.100096

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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 = "Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

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doi = "10.1016/j.xcrm.2020.100096",

language = "English (US)",

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T1 - Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection

AU - Hughes, Sean M.

AU - Levy, Claire N.

AU - Calienes, Fernanda L.

AU - Stekler, Joanne D.

AU - Pandey, Urvashi

AU - Vojtech, Lucia

AU - Berard, Alicia R.

AU - Birse, Kenzie

AU - Noël-Romas, Laura

AU - Richardson, Brian

AU - Golden, Jackelyn B.

AU - Cartwright, Michael

AU - Collier, Ann C.

AU - Stevens, Claire E.

AU - Curlin, Marcel E.

AU - Holtz, Timothy H.

AU - Mugo, Nelly

AU - Irungu, Elizabeth

AU - Katabira, Elly

AU - Muwonge, Timothy

AU - Lama, Javier R.

AU - Baeten, Jared M.

AU - Burgener, Adam

AU - Lingappa, Jairam R.

AU - McElrath, M. Juliana

AU - Mackelprang, Romel

AU - McGowan, Ian

AU - Cranston, Ross D.

AU - Cameron, Mark J.

AU - Hladik, Florian

PY - 2020/9/22

Y1 - 2020/9/22

N2 - 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.

AB - 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.

KW - ART

KW - HIV

KW - HIV cure

KW - ISG15

KW - antiretroviral treatment

KW - chronic immune activation

KW - gut

KW - interferon

KW - tenofovir

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U2 - 10.1016/j.xcrm.2020.100096

DO - 10.1016/j.xcrm.2020.100096

M3 - Article

C2 - 33015651

AN - SCOPUS:85096573619

SN - 2666-3791

VL - 1

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 6

M1 - 100096

ER -

Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection

Abstract

Keywords

ASJC Scopus subject areas

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