Web of Science: 3 citations, Scopus: 3 citations, Google Scholar: citations,
P-glycoprotein (ABCB1) activity decreases raltegravir disposition in primary CD4+P-gp high cells and correlates with HIV-1 viral load
Minuesa Dinarés, Gerard (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Arimany-Nardi, Cristina (National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBER EHD), Instituto de Salud Carlos III)
Erkizia, Itziar (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Cedeño, Samandhy (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Moltó Marhuenda, José (Institut Germans Trias i Pujol. Fundació de Lluita contra la Sida)
Clotet, Bonaventura (Institució Catalana de Recerca i Estudis Avançats (ICREA))
Pastor-Anglada, Marçal (National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBER EHD), Instituto de Salud Carlos III)
Martínez Picado, Francisco Javier (Universitat de Vic, Universitat Central de Catalunya (UVic-UCC))

Date: 2016
Abstract: To evaluate the role of P-glycoprotein (P-gp) and multidrug-resistant-protein 1 (MRP1) on raltegravir intracellular drug disposition in CD4+ T cells, investigate the effect of HIV-1 infection on P-gp expression and correlate HIV-1 viraemia with P-gp activity in primary CD4+ T cell subsets. The cellular accumulation ratio of [ 3 H]raltegravir was quantified in CD4+ T cell lines overexpressing either P-gp (CEM-P-gp) or MRP1 (CEM-MRP1) and in primary CD3+CD4+ T cells with high (P-gp high) and low P-gp activity (P-gp low); inhibition of efflux transporters was confirmed by the intracellular retention of calcein-AM. The correlation of P-gp activity with HIV-1 viraemia was assessed in naive and memory T cell subsets from 21 HIV-1-infected treatment-naive subjects. [ 3 H]Raltegravir cellular accumulation ratio decreased in CEM-P-gp cells (P < 0. 0001). XR9051 (a P-gp inhibitor) and HIV-1 PIs reversed this phenomenon. Primary CD4+P-gp high cells accumulated less raltegravir (38. 4% ± 9. 6%) than P-gp low cells, whereas XR9051 also reversed this effect. In vitro HIV-1 infection of PBMCs and stimulation of CD4+ T cells increased P-gp mRNA and P-gp activity, respectively, while primary CD4+P-gp high T cells sustained a higher HIV-1 replication than P-gp low cells. A significant correlation between HIV-1 viraemia and P-gp activity was found in different CD4+ T cell subsets, particularly memory CD4+ T cells (r = 0. 792, P < 0. 0001). Raltegravir is a substrate of P-gp in CD4+ T cells. Primary CD4+P-gp high T cells eliminate intracellular raltegravir more readily than P-gp low cells and HIV-1 viraemia correlates with P-gp overall activity. Specific CD4+P-gp high T cell subsets could facilitate the persistence of viral replication in vivo and ultimately promote the appearance of drug resistance.
Note: Número d'acord de subvenció CE/FP7/2007–2013/CHAIN/223131
Note: Número d'acord de subvenció RD12/0017/0002
Note: Número d'acord de subvenció SAF2014-25560-R
Note: Número d'acord de subvenció AGAUR/2013FI_B 00275
Rights: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. Creative Commons
Language: Anglès.
Document: article ; recerca ; publishedVersion
Published in: Journal of Antimicrobial Chemotherapy, Vol. 71 (june 2016) , p. 2782-2792, ISSN 1460-2091

PMID: 27334660
DOI: 10.1093/jac/dkw215


11 p, 635.6 KB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (scientific output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles

 Record created 2018-02-07, last modified 2019-10-02



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