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In vitro exposure of leukocytes to HIV pre-exposure prophylaxis
(PrEP) decreases mitochondrial function and
alters gene expression profiles.
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AAC Accepted Manuscript Posted Online 5 October 2020Antimicrob. Agents Chemother.
Emily R. Bowman1, Cheryl Cameron2,Brian Richardson2, Manjusha Kulkarni1, Janelle 4Gabriel1, Aaren Kettelhut1, Lane Hornsby1, Jesse J. Kwiek1, Abigail Norris Turner1, 5Carlos Malvestutto1, Jose Bazan1, Susan L. Koletar1, Susanne Doblecki-Lewis3,Michael 6M. Lederman2, Mark Cameron2, Nichole R. Klatt4, Jordan E. Lake5, Nicholas T. 7Funderburg
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ABSTRACT
Background: The use of antiretroviral therapy (ART) as pre-exposure 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.
Methods: 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 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 RNAseq. Plasma lipids were measured using mass spectrometry.
Results: 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.
Conclusions: 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.
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