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Functional correlation of P-glycoprotein expression and genotype with expression of the human immunodeficiency virus type 1 coreceptor CXCR4

Owen, A., Chandler, B., Bray, Patrick, Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192, Hart, C. Anthony, Back, D. J. and Khoo, S. H. (2004) 'Functional correlation of P-glycoprotein expression and genotype with expression of the human immunodeficiency virus type 1 coreceptor CXCR4'. Journal of Virology, Vol 78, Issue 21, pp. 12022-12029.

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Abstract

The aim of this study was to investigate the relationship between lymphocyte P-glycoprotein (P-gp) expression and genotype in vivo and the expression of lymphocyte receptors critical in the life cycle of human immunodeficiency virus type 1 (HIV-1), i.e., CD4, CCR5, and CXCR4. Using flow cytometry to quantify each membrane receptor/transporter, we demonstrate a highly significant correlation between P-gp protein expression and the expression of CXCR4 (rho = 0.874; P < 0.0001). Furthermore, confocal microscopy showed colocalized expression of CXCR4 and P-gp in the lymphocyte membrane. This significant relationship was also apparent at the mRNA level by use of reverse transcription-PCR (rho = 0.61; P < 0.005) and was present in both phytohemagglutinin-stimulated and unstimulated peripheral blood mononuclear cells. Genotypic analysis of the C3435T single-nucleotide polymorphism of P-gp confirmed significantly higher levels of P-gp in C (range, 2.45 to 11.00 relative fluorescence units [RFU])- than in T (range, 0.25 to 5.00 RFU)-homozygous individuals (P = 0.0088; 95% confidence interval [95% CI], 0.7 to 6.3 RFU). An equivalent association between CXCR4 levels and C (range, 12.7 to 44.1 RFU) versus T (range, 3 to 18.9 RFU) genotype was also demonstrated (P = 0.0019; 95% CI, 5.4 to 23.7). Functionally, although these correlates had no impact on HIV-1 production from either X4- or R5-tropic virus, expression correlated significantly with the activity of the HIV-1 protease inhibitor (PI) saquinavir for both P-gp (rho = 0.75; P = 0.0019) and CXCR4 (rho = 0.71; P = 0.0041). This study defines an association between P-gp (expression and genotype) and CXCR4 that may have implications for the selection of viral tropism and the access of drugs to protease for specific tropic types. The interplay between these two proteins may also influence the viral genotypes which escape effective chemotherapy and which therefore have the opportunity to evolve resistance to PIs.

Item Type: Article
Uncontrolled Keywords: active antiretroviral therapy vascular endothelial-cells blood mononuclear-cells human lymphoid-tissue multidrug-resistance protease inhibitors hiv-1-infected individuals in-vitro selective-inhibition disease progression
Subjects: QW Microbiology and Immunology > QW 45 Microbial drug resistance. General or not elsewhere classified.
WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503 Acquired immunodeficiency syndrome. HIV infections
WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503.2 Therapy
WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503.6 Prevention and control
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1128/JVI.78.21.12022-12029.2004
Depositing User: Sarah Lewis-Newton
Date Deposited: 08 Feb 2012 13:39
Last Modified: 06 Feb 2018 13:03
URI: http://archive.lstmed.ac.uk/id/eprint/2188

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