Abstract
| Original language | English |
|---|---|
| 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 |
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Keywords
- efflux drug transporters
- uptake drug transporters
- gene expression
- CD4+ T cells
- α4β7 integrin
- colorectal mucosa
Cite this
Transporters for Antiretroviral Drugs in Colorectal CD4+ T Cells and Circulating α4β7 Integrin CD4+ T cells : Implications for HIV Microbicides. / Mukhopadhya, Indrani; Murray, Graeme I; Duncan, Linda; Yuecel, Raif; Shattock, Robin; Kelly, Charles ; Iannelli, Francesco ; Pozzi, Gianni; El-Omar, Emad; Hold, Georgina; Hijazi, Karolin.
In: Molecular Pharmaceutics, Vol. 13, No. 9, 06.09.2016, p. 3334-3340.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Transporters for Antiretroviral Drugs in Colorectal CD4+ T Cells and Circulating α4β7 Integrin CD4+ T cells
T2 - Implications for HIV Microbicides
AU - Mukhopadhya, Indrani
AU - Murray, Graeme I
AU - Duncan, Linda
AU - Yuecel, Raif
AU - Shattock, Robin
AU - Kelly, Charles
AU - Iannelli, Francesco
AU - Pozzi, Gianni
AU - El-Omar, Emad
AU - Hold, Georgina
AU - Hijazi, Karolin
N1 - This work was supported by the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement No 305316 as part of the MOTIF (Microbicides Optimisation Through Innovative Formulation for Vaginal and Rectal Delivery) project. We would like to extend our thanks to all the study participants for their invaluable contribution and to Grampian Biorepository staff for help with collection of fresh colorectal resection tissue.
PY - 2016/9/6
Y1 - 2016/9/6
N2 - 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.
AB - 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.
KW - efflux drug transporters
KW - uptake drug transporters
KW - gene expression
KW - CD4+ T cells
KW - α4β7 integrin
KW - colorectal mucosa
U2 - 10.1021/acs.molpharmaceut.6b00351
DO - 10.1021/acs.molpharmaceut.6b00351
M3 - Article
VL - 13
SP - 3334
EP - 3340
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 9
ER -