TY - JOUR
T1 - In vitro exposure of leukocytes to HIV preexposure prophylaxis decreases mitochondrial function and alters gene expression profiles
AU - Bowman, Emily R.
AU - Cameron, Cheryl
AU - Richardson, Brian
AU - Kulkarni, Manjusha
AU - Gabriel, Janelle
AU - Kettelhut, Aaren
AU - Hornsby, Lane
AU - Kwiek, Jesse J.
AU - Turner, Abigail Norris
AU - Malvestutto, Carlos
AU - Bazan, Jose
AU - Koletar, Susan L.
AU - Doblecki-Lewis, Susanne
AU - Lederman, Michael M.
AU - Cameron, Mark
AU - Klatt, Nichole R.
AU - Lake, Jordan E.
AU - Funderburg, Nicholas T.
N1 - Funding Information:
This work was supported by the National Institutes of Health (R01HL134544 to N.T.F.).
Funding Information:
Research reported in this publication was supported by The Ohio State University Comprehensive Cancer Center and the National Institutes of Health under grant number P30 CA016058. The project described was supported by award number UL1TR002733 from the National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
Publisher Copyright:
© 2020 Bowman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/1
Y1 - 2021/1
N2 - The use of antiretroviral therapy (ART) as preexposure prophylaxis (PrEP) is an effective strategy for preventing HIV acquisition. The cellular consequences of PrEP exposure, however, have not been sufficiently explored to determine potential effects on health in individuals without HIV. In this study, peripheral blood mononuclear cells (PBMCs) from people without HIV were exposed to tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC) overnight. Mitochondrial mass and function were measured by flow cytometry and an Agilent XFp analyzer. Monocyte-derived macrophages (MDMs) were differentiated in 20% autologous serum for 5 days in the presence or absence of TDF or FTC, and surface markers, lipid uptake, and efferocytosis were measured by flow cytometry. MDM gene expression was measured using transcriptome sequencing (RNA-seq). Plasma lipids were measured using mass spectrometry. PBMCs exposed to TDF or FTC had decreased maximal oxygen consumption rate (OCR) and reduced mitochondrial mass. Exposure to PrEP also increased reactive oxygen species (ROS) production from monocyte subsets. Compared to MDMs cultured in medium alone, cells differentiated in the presence of TDF (829 genes) or FTC (888 genes) had significant changes in gene expression. Further, PrEP-exposed MDMs had decreased mitochondrial mass and displayed increased lipid uptake and reduced efferocytosis. Plasma biomarkers and lipid levels were also altered in vivo in individuals receiving a PrEP regimen. In conclusion, exposure of leukocytes to TDF or FTC resulted in decreased mitochondrial function and altered functional and transcriptional profiles. These findings may have important implications for the metabolic and immunologic consequences of PrEP in populations at risk for HIV acquisition.
AB - The use of antiretroviral therapy (ART) as preexposure prophylaxis (PrEP) is an effective strategy for preventing HIV acquisition. The cellular consequences of PrEP exposure, however, have not been sufficiently explored to determine potential effects on health in individuals without HIV. In this study, peripheral blood mononuclear cells (PBMCs) from people without HIV were exposed to tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC) overnight. Mitochondrial mass and function were measured by flow cytometry and an Agilent XFp analyzer. Monocyte-derived macrophages (MDMs) were differentiated in 20% autologous serum for 5 days in the presence or absence of TDF or FTC, and surface markers, lipid uptake, and efferocytosis were measured by flow cytometry. MDM gene expression was measured using transcriptome sequencing (RNA-seq). Plasma lipids were measured using mass spectrometry. PBMCs exposed to TDF or FTC had decreased maximal oxygen consumption rate (OCR) and reduced mitochondrial mass. Exposure to PrEP also increased reactive oxygen species (ROS) production from monocyte subsets. Compared to MDMs cultured in medium alone, cells differentiated in the presence of TDF (829 genes) or FTC (888 genes) had significant changes in gene expression. Further, PrEP-exposed MDMs had decreased mitochondrial mass and displayed increased lipid uptake and reduced efferocytosis. Plasma biomarkers and lipid levels were also altered in vivo in individuals receiving a PrEP regimen. In conclusion, exposure of leukocytes to TDF or FTC resulted in decreased mitochondrial function and altered functional and transcriptional profiles. These findings may have important implications for the metabolic and immunologic consequences of PrEP in populations at risk for HIV acquisition.
KW - Human immunodeficiency virus
KW - Inflammation
KW - Leukocytes
KW - Lipids
KW - Mitochondrial dysfunction
KW - Preexposure prophylaxis
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U2 - 10.1128/AAC.01755-20
DO - 10.1128/AAC.01755-20
M3 - Article
C2 - 33020165
AN - SCOPUS:85098666719
VL - 65
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 1
M1 - e01755-20
ER -