Abstract
CD4+ T lymphocytes in the colorectal mucosa are key in HIV-1 transmission and dissemination. As such they are also the primary target for anti-retroviral (ARV)-based rectal microbicides for pre-exposure prophylaxis. Drug transporters expressed in mucosal CD4+ T cells determine ARV distribution across the cell membrane and, most likely, efficacy of microbicides. We describe transporters for antiretroviral drugs in colorectal mucosal CD4+ T lymphocytes and compare gene expression with circulating α4β7+CD4+ T cells which traffic to the intestine and have been shown to be preferentially infected by HIV-1. Purified total CD4+ T cells were obtained from colorectal tissue and blood samples by magnetic separation. CD4+ T cells expressing α4β7 integrin were isolated by fluorescence-activated cell sorting from peripheral blood mononuclear cells of healthy volunteers. Expressions of 15 efflux and uptake drug transporter genes were quantified using Taqman qPCR assays. Expression of efflux transporters MRP3, MRP5, BCRP and uptake transporter CNT2 was significantly higher in colorectal CD4+ T cells compared to circulating CD4+ T cells (p=0.01-0.03). Conversely, circulating α4β7+CD4+ T cells demonstrated significantly higher expression of OATPD compared to colorectal CD4+ T cells (p=0.001). To the best of our knowledge this is the first report of drug transporter gene expression in colorectal CD4+ and peripheral α4β7+CD4+ T cells. The qualitative and quantitative differences in drug transporter gene expression profiles between α4β7+CD4+ T cells and total mucosal CD4+ T cells may have significant implications for the efficacy of rectally delivered ARV-microbicides. Most notably, we have identified efflux drug transporters that could be targeted by selective inhibitors or beneficial drug-drug interactions to enhance intracellular accumulation of antiretroviral drugs.
Original language | English |
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Pages (from-to) | 3334-3340 |
Number of pages | 7 |
Journal | Molecular Pharmaceutics |
Volume | 13 |
Issue number | 9 |
Early online date | 28 Jul 2016 |
DOIs | |
Publication status | Published - 6 Sep 2016 |
Keywords
- efflux drug transporters
- uptake drug transporters
- gene expression
- CD4+ T cells
- α4β7 integrin
- colorectal mucosa
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Profiles
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Karolin Hijazi
- School of Medicine, Medical Sciences & Nutrition, Dental Education - Senior Clinical Lecturer
- Institute of Medical Sciences
- Clinical Medicine
Person: Clinical Academic
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BD Influx Cell Sorter
Andrea Holme (Manager)
Iain Fraser Cytometry CentreResearch Facilities: Equipment
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Iain Fraser Cytometry Centre
Andrea Holme (Manager), Linda Duncan (Senior Application Scientist), Ailsa Laird (Technician) & Kate Burgoyne (Technician)
Institute of Medical SciencesResearch Facilities: Facility