TY - JOUR
T1 - Antiretroviral Drug Transporters and Metabolic Enzymes in Circulating Monocytes and Monocyte-Derived Macrophages of ART-Treated People Living with HIV and HIV-Uninfected Individuals
AU - Hoque, Tozammel M.D.
AU - Cattin, Amélie
AU - Whyte-Allman, Sana Kay
AU - Winchester, Lee
AU - Fletcher, Courtney V.
AU - Routy, Jean Pierre
AU - Ancuta, Petronela
AU - Bendayan, Reina
N1 - Funding Information:
Supported by the University of Toronto, Leslie Dan Faculty of Pharmacy Internal Grant 923465 (to R.B.), the Canadian HIV Cure Enterprise Team Grant (CanCURE 1.0) funded by the Canadian Institutes of Health Research (CIHR) in partnership with CANFAR and IAS HIG-133050 (to P.A.), and the National Institute of Allergy and Infectious Diseases Grant 1R01 AI-124965 (to C.V.F.). This study was also funded by the CIHR Grants MOP 103230 and PTJ 166049; the Vaccines and Immunotherapy Core of the CIHR Canadian HIV Trials Network Grant CTN 257 and CTN PT027 (to J.-P.R.), and the CIHR-funded CanCURE 2.0 Team Grant HB2-164064 (to P.A. and J.-P.R.). S.-K.W.-A. is the recipient of the University of Toronto Connaught International scholarship.
Publisher Copyright:
© 2021 Lippincott Williams and Wilkins. All rights reserved.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - Membrane-associated drug transport proteins and drug metabolic enzymes could regulate intracellular antiretroviral (ARV) drug concentrations in HIV-1 target cells such as myeloid cells. We investigated the expression of these transporters and enzymes in monocyte subsets and monocyte-derived macrophages (MDMs) isolated from peripheral blood mononuclear cells (PBMCs) of HIV-uninfected individuals (HIV-negative) and people living with HIV receiving viral suppressive antiretroviral therapy (ART; HIV+ART) and examined plasma and intracellular ARV concentrations. Monocytes were isolated from PBMCs of 12 HIV-negative and 12 HIV+ART donors and differentiated into MDMs. The mRNA and protein expression of drug transporters and metabolic enzymes were analyzed by quantitative real-time polymerase chain reaction and flow cytometry, respectively. ARV drug concentrations were quantified in plasma, PBMCs, monocytes, and MDMs by LC-MS/MS. The mRNA expression of relevant ARV transporters or metabolic enzymes, ABCB1/P-gp, ABCG2/BCRP, ABCC1/MRP1, ABCC4/MRP4, SLC22A1/OCT1, SLC29A2/ENT2, CYP2B6, CYP2D6, and UGT1A1, was demonstrated in monocytes and MDMs of 2 to 4 HIV-negative donors. P-gp, BCRP, and MRP1 proteins were differentially expressed in classical, intermediate, and nonclassical monocytes and MDMs of both HIV+ART and HIV-negative donors. Intracellular concentrations of ARVs known to be substrates of these transporters and metabolic enzymes were detected in monocytes of HIV+ART donors but were undetectable in MDMs. In this study, we demonstrated the expression of drug transporters and metabolic enzymes in monocytes and MDMs of HIV-negative and HIV+ART individuals, which could potentially limit intracellular concentrations of ARVs and contribute to residual HIV replication. Further work is needed to assess the role of these transporters in the penetration of ARVs in tissue macrophages.
AB - Membrane-associated drug transport proteins and drug metabolic enzymes could regulate intracellular antiretroviral (ARV) drug concentrations in HIV-1 target cells such as myeloid cells. We investigated the expression of these transporters and enzymes in monocyte subsets and monocyte-derived macrophages (MDMs) isolated from peripheral blood mononuclear cells (PBMCs) of HIV-uninfected individuals (HIV-negative) and people living with HIV receiving viral suppressive antiretroviral therapy (ART; HIV+ART) and examined plasma and intracellular ARV concentrations. Monocytes were isolated from PBMCs of 12 HIV-negative and 12 HIV+ART donors and differentiated into MDMs. The mRNA and protein expression of drug transporters and metabolic enzymes were analyzed by quantitative real-time polymerase chain reaction and flow cytometry, respectively. ARV drug concentrations were quantified in plasma, PBMCs, monocytes, and MDMs by LC-MS/MS. The mRNA expression of relevant ARV transporters or metabolic enzymes, ABCB1/P-gp, ABCG2/BCRP, ABCC1/MRP1, ABCC4/MRP4, SLC22A1/OCT1, SLC29A2/ENT2, CYP2B6, CYP2D6, and UGT1A1, was demonstrated in monocytes and MDMs of 2 to 4 HIV-negative donors. P-gp, BCRP, and MRP1 proteins were differentially expressed in classical, intermediate, and nonclassical monocytes and MDMs of both HIV+ART and HIV-negative donors. Intracellular concentrations of ARVs known to be substrates of these transporters and metabolic enzymes were detected in monocytes of HIV+ART donors but were undetectable in MDMs. In this study, we demonstrated the expression of drug transporters and metabolic enzymes in monocytes and MDMs of HIV-negative and HIV+ART individuals, which could potentially limit intracellular concentrations of ARVs and contribute to residual HIV replication. Further work is needed to assess the role of these transporters in the penetration of ARVs in tissue macrophages.
KW - HIV reservoirs
KW - antiretroviral drugs
KW - drug metabolic enzymes
KW - drug transporters
KW - macrophages
KW - monocytes
UR - http://www.scopus.com/inward/record.url?scp=85108988272&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85108988272&partnerID=8YFLogxK
U2 - 10.1097/QAI.0000000000002682
DO - 10.1097/QAI.0000000000002682
M3 - Article
C2 - 34153016
AN - SCOPUS:85108988272
SN - 1525-4135
VL - 87
SP - 1093
EP - 1101
JO - Journal of Acquired Immune Deficiency Syndromes
JF - Journal of Acquired Immune Deficiency Syndromes
IS - 4
ER -