title: Transporters for Antiretroviral Drugs in Colorectal CD4+ T Cells and Circulating α4β7 Integrin CD4+ T Cells: Implications for HIV Microbicides.
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 antiretroviral (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, and BCRP and uptake transporter CNT2 were 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.
authors.affiliation: University of Aberdeen Dental School and Hospital , Aberdeen AB25 2ZR, U.K.|Institute of Medical Sciences, University of Aberdeen , Aberdeen AB25 2ZD, U.K.
authors.forename: Indrani
authors.initials: I
authors.lastname: Mukhopadhya
authors.affiliation: Department of Pathology, School of Medicine & Dentistry, University of Aberdeen , Aberdeen AB25 2ZD, U.K.
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Murray
authors.affiliation: Institute of Medical Sciences, University of Aberdeen , Aberdeen AB25 2ZD, U.K.
authors.forename: Linda
authors.initials: L
authors.lastname: Duncan
authors.affiliation: Institute of Medical Sciences, University of Aberdeen , Aberdeen AB25 2ZD, U.K.
authors.forename: Raif
authors.initials: R
authors.lastname: Yuecel
authors.affiliation: Mucosal Infection & Immunity Group, Section of Infectious Diseases, Imperial College , London W2 1PG, U.K.
authors.forename: Robin
authors.initials: R
authors.lastname: Shattock
authors.affiliation: Mucosal & Salivary Biology, King's College London, Dental Institute , London SE1 1UL, U.K.
authors.forename: Charles
authors.initials: C
authors.lastname: Kelly
authors.affiliation: Laboratory of Molecular Microbiology and Biotechnology, Department of Medical Biotechnologies, University of Siena , Siena 53100, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Iannelli
authors.affiliation: Laboratory of Molecular Microbiology and Biotechnology, Department of Medical Biotechnologies, University of Siena , Siena 53100, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Pozzi
authors.affiliation: Institute of Medical Sciences, University of Aberdeen , Aberdeen AB25 2ZD, U.K.
authors.forename: Emad M
authors.initials: EM
authors.lastname: El-Omar
authors.affiliation: Institute of Medical Sciences, University of Aberdeen , Aberdeen AB25 2ZD, U.K.
authors.forename: Georgina L
authors.initials: GL
authors.lastname: Hold
authors.affiliation: University of Aberdeen Dental School and Hospital , Aberdeen AB25 2ZR, U.K.|Institute of Medical Sciences, University of Aberdeen , Aberdeen AB25 2ZD, U.K.
authors.forename: Karolin
authors.initials: K
authors.lastname: Hijazi
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D016023:Integrins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; C071777:integrin alpha4beta7
keywords: CD4+ T cells; colorectal mucosa; efflux drug transporters; gene expression; uptake drug transporters; α4β7 integrin