Background:  The potential contribution of lymphocyte drug transporters to inter-individual variation in response to ART is under investigation. Some human nucleoside transporters (hENT1-4 and hCNT1) facilitate influx of nucleosides and nucleoside reverse transcriptase inhibitors (NRTI). Certain abacavir (ABC) transporters mediate efflux of protease inhibitors (PI) (P-gp, MRP1, and MRP2) or nucleoside reverse transcriptase inhibitors (NRTI) (MRP4 and MRP5). The nuclear receptor PXR (NR1l2) contributes to P-gp RNA regulation in vitro. We investigated whether expression of these influx and efflux transporters, and the P-gp regulator (PXR), varied in CD4⁺ lymphocytes in vivo based on HIV-1 infection or ART.

Methods:  RNA from CD4⁺ cells of 10 HIV^– and 13 HIV⁺, ART-naive subjects was quantified by TaqMan Low Density Arrays (LDA) (ABI) before, and at both 3 and 6 months after starting ART. Statistical significance was evaluated by Mann-Whitney U test.

Results:  Expression of P-gp, MRP5, hENT2, and hENT3 was significantly lower in the HIV-infected, ART-naïve subjects’ cells than in cells from HIV^– subjects (p ≤0.05 for each). The levels of MRP5 and hENT3 RNA were increased from pre-ART baseline, and no different from the level in HIV^– subjects’ cells after 3 months of therapy (p = 0.6 for both). A strong correlation between P-gp and PXR RNA was found (Spearman r = 0.62, p = 0.003). Expression of hCNT1, hCNT3, and hENT4 was undetectable in CD4⁺ lymphocytes, and hENT1 was expressed at very low levels. P-gp, MRP4, hENT2, and NR1l2 RNA presented a wider range across subjects than MRP1, 4 and 5 RNA.

Conclusions:  Expression of drug transporters varied among individuals. We have begun to define which NRTI influx transporters are expressed in CD4⁺ lymphocytes and confirmed an association between PXR and P-gp levels in vivo. HIV infection down-modulates P-gp, MRP5, hENT2, and hENT3 RNA, but their levels became comparable to those of HIV^– subjects’ cells after ART. This suggests that changes in levels of transporters after starting therapy may potentially decrease intracellular concentrations of PI, and increase that of NRTI.