Background:  P-glycoprotein (P-gp) is a cellular efflux pump encoded by MDR1. It is present in various tissues and cells including T lymphocytes. Currently approved HIV-1 protease inhibitors (PI) are substrates for P-gp. It has been suggested that allelic variants of MDR1 influence response to antiretroviral therapy (ART), although study results have been inconsistent. In addition, PI can inhibit P-gp activity ex vivo and induce P-gp expression in cultured cells.  Our previous data suggested that nelfinavir may partially inhibit T lymphocyte P-gp activity in vivo. The present study examined relationships between antiretroviral therapy (ART) and P-gp functional activity on CD4⁺ T cells according to MDR1 genotype.

Methods:  Samples were obtained from HIV-1 infected persons during routine care.  P-gp activity was quantified using the fluorescent P-gp substrate dye 3,3'-diethyloxacarbocyanine iodide. CD4⁺  T cells were identified by flow cytometry and efflux activity was corrected for background activity after inhibition by 19 µM verapamil. Exon 26 (C3435T) and exon 21 (G2677T/A) single nucleotide polymorphisms were identified by real-time PCR. Clinical data was obtained by retrospective review of computerized charts. Student’s t-test and ANOVA were used to compare mean P-gp efflux activity and clinical variables across groups.

Results:  CD4⁺ T-cell P-gp activity and MDR1 genotype were determined in 205 HIV-infected subjects including 47 (20%) females and 64 (28%) African Americans. A total of 148 (72%) was receiving ART, which included a PI in 78 (38%). Among 44 subjects with the T/T genotype at position C3435T, mean CD4 T cell P-gp activity was 8.4±5.7% in those receiving a PI vs 15.3±9.8% in those on ART but no PI (p = 0.04), and vs 13.4±5.4% in those not receiving ART (p = 0.02). Among all subjects receiving a PI, CD4⁺ T-cell P-gp activity was lower in those with the T/T vs C/C genotype (8.4±5.7% vs 13.6±7.7%, respectively; p = 0.04). Exon 21 genotype did not predict P-gp activity. Absolute CD4⁺ T-cell counts and plasma HIV-1 RNA levels did not differ by genotype.

Conclusions:  CD4⁺ T-cell P-gp activity in patients receiving treatment with a PI may be differentially influenced by MDR1 genotype, with persons having the exon 26 T/T genotype demonstrating significantly lower activity compared to those with the C/C genotype. This could contribute to the reported relationships between MDR1 genotype and response to ART.

Keywords: MDR1; P-glycoprotein; protease inhibitors