1. In Vitro Exposure of Leukocytes to HIV Preexposure Prophylaxis Decreases Mitochondrial Function and Alters Gene Expression Profiles
- Author
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Lane Hornsby, Jose A. Bazan, Manjusha Kulkarni, Michael M. Lederman, Nicholas T. Funderburg, Jordan E. Lake, Aaren Kettelhut, Jesse J. Kwiek, Brian Richardson, Susanne Doblecki-Lewis, Mark J. Cameron, Carlos Malvestutto, Cheryl M. Cameron, Abigail Norris Turner, Nichole R. Klatt, Susan L. Koletar, Janelle Gabriel, and Emily R. Bowman
- Subjects
leukocytes ,preexposure prophylaxis ,Inflammation ,Emtricitabine ,Peripheral blood mononuclear cell ,Antiviral Agents ,Flow cytometry ,Andrology ,lipids ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Gene expression ,mitochondrial dysfunction ,medicine ,Pharmacology (medical) ,030212 general & internal medicine ,Efferocytosis ,030304 developmental biology ,Pharmacology ,chemistry.chemical_classification ,0303 health sciences ,Reactive oxygen species ,medicine.diagnostic_test ,human immunodeficiency virus ,business.industry ,virus diseases ,Infectious Diseases ,chemistry ,inflammation ,medicine.symptom ,business ,medicine.drug - Abstract
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., 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.
- Published
- 2020