Expression levels of MDR1, MRP1, MRP4, and MRP5 in peripheral blood mononuclear cells from HIV infected patients failing antiretroviral therapy

Abstract

The aim of the study was to evaluate the mRNA expression of four relevant ABC-transporter genes [MDR1 (P-glycoprotein; Pgp), MRP1, MRP4, and MRP5] in HIV-positive individuals failing treatment and analyze the association between the levels of their expression and viral load, CD4 cell count, and therapeutic history. Ninety-eight HIV-positive samples and 20 samples from healthy donors were analyzed, retrospectively. Peripheral blood mononuclear cells (PBMCs) from HIV1-positive individuals were collected at the time of virological failure. Expression of mRNA of Pgp, MRP1, MRP4, and MRP5 in PBMCs was evaluated by real-time PCR. A high inter-individual variability was observed in both HIV-positive individuals and healthy donors but the expression levels of all mRNA analyzed were significantly higher in the HIV-infected group (P < 0.05). A weak but significant inverse correlation was observed between CD4 cell counts and expression levels of MRP4 and MRP5. Comparison of mRNA expression between individuals with different therapeutic histories showed that expression of MRP4 and MRP5 genes in patients who were both protease inhibitor (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI)-experienced was significantly higher than in patients who were PI experienced but NNRTI-naïve. In conclusion, the mRNA expression of Pgp, MRP1, MRP4, and MRP5 varies among HIV-infected patients and healthy donors but is significantly higher in HIV-positive patients than in donors. The expression of MRP4 and MRP5 seems to correlate with CD4 cell counts. The same protein seems to be overexpressed in patients receiving NNRTIs.

The Dual Role of Pharmacogenetics in HIV Treatment: Mutations and Polymorphisms Regulating Antiretroviral Drug Resistance and Disposition

“…This efflux transporter is widely distributed and has significant expression levels in the small intestine, liver, kidneys, and brain (Ho and Kim, 2005). It is also expressed in other tissues, such as the placenta, ovaries, testicles, and lymphocytes (Thiebaut et al, 1987;Cordon-Cardo et al, 1989;Klimecki et al, 1994;Turriziani et al, 2008). ABCB1 expression in lymphocytes has been observed in 20 to 80% of B lymphocytes and 30 to 80% of T cells (Chaudhary et al, 1992;Drach et al, 1992;Klimecki et al, 1994;Ludescher et al, 1998;Köck et al, 2007).…”

“…It has been reported that ABCC1 and ABCC2 transporter expression was higher in CD4 ϩ cells, followed by CD8 ϩ and CD19 ϩ cells (Oselin et al, 2003). Briefly stated, mRNA or the protein was detected for the various ABCC1, -2, -4, and -5 transporters in monocytes, CD4 ϩ cell lines, and the lymphocytes of patients infected with HIV (Oselin et al, 2003;Zhang et al, 2006;Turriziani et al, 2008;Weiss et al, 2009).…”

The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

“…MRP4 is widely expressed in a range of human blood cells including CD34 ? stem cells, erythrocytes, platelets, granulocytes and lymphocytes [24,25]. MRP4 is localized in the plasma membrane and shows an ATPdependent transport of a broad range of compounds.…”

Comparative description of haplotype structure and genetic diversity of MDR1 (ABCB1) in HIV-positive and HIV-negative populations

“…We have two main reasons to pursue these aims: first, it has been shown that MDR1 locus has recently undergone positive selection, most likely due to environmental factors, which may include xenobiotics and pathogens (Tang et al, 2004; Wang et al, 2007). Although, to our knowledge, no report has indicated genetic changes in MDR1 associated with HIV, HIV-infected patients showed a significant increase in P-gp expression in CD4 + and CD8 + T cells (Andreana et al, 1996), in MDR1 mRNA levels and P-gp expression in placentas (Camus et al, 2006), and in MDR1 mRNA levels in peripheral blood mononuclear cells (PBMCs) (Turriziani et al, 2008). In this study, we sought to determine whether MDR1 genetic characteristics are similar or different between HIV-positive and HIV-negative individuals.…”