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Background:  P-glycoprotein (P-gp) is the cellular efflux transporter encoded by MDR1. Its expression in various tissues affects oral absorption, elimination, and tissue penetration of diverse compounds. T lymphocytes also express P-gp and HIV protease inhibitors (PI) are P-gp substrates. Inter-individual variability in P-gp activity in lymphocytes may therefore affect response to antiretroviral therapy (ART). We characterized CD4⁺ lymphocyte P-gp activity, MDR1 polymorphisms, and clinical/demographic factors in HIV-infected adults, with the hypothesis that inter-individual variability in P-gp activity would be associated with MDR1 single nucleotide polymorphisms (SNP).

Methods:  Specimens were obtained from HIV-infected adults during routine clinical care between April 2002 and July 2003. Total and naïve CD4⁺ lymphocytes were identified by flow cytometry. P-gp activity was quantified based on proportion of cells effluxing the fluorescent substrate dye DiOC₂(3). MDR1 exon 26 (C3435T) and exon 21 (G2677T/A) SNP were identified by real-time PCR and oligonucleotide ligation. Clinical data was abstracted from electronic medical records. Analyses included Wilcoxon rank-sum and Kruskal-Wallis tests, and multivariate linear regression.

Results:  CD4⁺ lymphocyte P-gp activity and MDR1 genotype were determined in 313 HIV-infected subjects including 62 (20%) females, 209 (67%) Caucasians, and 95 (30%) African Americans. A total of 217 (69%) were receiving ART, including a PI in 118 (54%). Median (IQR) P-gp efflux activity was 12% (8% to 18%) and 24% (16% to 34%) in total and naïve CD4⁺ lymphocyte populations, respectively. MDR1 SNP at positions C3435T or G2677T/A did not predict CD4⁺ lymphocyte P-gp activity. In contrast, median naive CD4⁺ lymphocyte P-gp activity was significantly higher in African Americans than in Caucasians (29 vs 22%; p = 0.002), with a trend toward higher activity in African American males than African American females (31 vs 24%; p = 0.05). Independent predictors of higher naïve CD4⁺ lymphocyte P-gp activity included African American race and male gender.

Conclusions:  We report the novel observation that naïve CD4⁺ lymphocyte P-gp activity was significantly higher in African Americans than in Caucasians. The lack of association with the SNP studied here suggests that variability in P-gp activity may be due to other MDR1 SNP, or yet to be identified clinical factors. Continued study of implications of P-gp for HIV and its therapy is warranted.

Keywords: MDR1; P-glycoprotein; Population groups