Transporters for Antiretroviral Drugs in Colorectal CD4+ T Cells and Circulating α4β7 Integrin CD4+ T cells

Implications for HIV Microbicides

Indrani Mukhopadhya, Graeme I Murray, Linda Duncan, Raif Yuecel, Robin Shattock, Charles Kelly, Francesco Iannelli, Gianni Pozzi, Emad El-Omar, Georgina Hold, Karolin Hijazi

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)3334-3340
Number of pages7
JournalMolecular Pharmaceutics
Volume13
Issue number9
Early online date28 Jul 2016
DOIs
Publication statusPublished - 6 Sep 2016

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Anti-Infective Agents
Integrins
HIV
T-Lymphocytes
Pharmaceutical Preparations
HIV-1
Gene Expression
Drug Interactions
Transcriptome
Intestines
Blood Cells
Healthy Volunteers
Flow Cytometry
Mucous Membrane
Cell Membrane

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 journalArticle

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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.",
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AU - Hijazi, Karolin

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