P-glycoprotein (P-gp) transports a wide range of structurally unrelated drugs, such as
HIV protease inhibitors (PIs) and cytotoxic compounds such as
anthracyclines. Because modification of P-gp phenotype and function is an important underlying mechanism of drug interactions, the current study was conducted in order to evaluate whether
highly active antiretroviral therapy (
HAART), HIV plasma viral load (VL), or
cancer chemotherapy may induce in vivo changes of P-gp phenotype in peripheral blood mononuclear cells (PBMCs) from HIV-infected treatment-naive and -experienced subjects at different stages of
HIV infection and/or disease, including patients with HIV-associated
Kaposi sarcoma (KS). Our results show that neither
HAART nor HIV VL, nor the stage of
HIV infection and/or disease, significantly alter P-gp expression on PBMCs. In particular, surface P-gp expression is expressed at low levels by T-cell subsets, B cells, and NK cells, whereas almost all monocytes are double positive and these results are not modified by HIV PI-containing regimens. By contrast, a significant phenotype modification is detected in PBMCs from
AIDS/KS patients after challenge with the liposomal formulation of the
anthracycline doxorubicin (L-DOX) with the higher expression reached 24 hours after the end of the
drug infusion. In addition, accumulation of L-DOX is unaffected by P-gp-mediated
drug efflux as documented by in vitro experiments, in sharp contrast to the kinetic of free DOX, based on HIV PI blockade experiments. Finally, P-gp expression was found in KS spindle cells from HIV-infected treatment-naive
AIDS/KS patients. We conclude that P-gp phenotype in PBMCs and specific subsets is not altered by
HAART and/or HIV, whereas a significant increase is induced by specific anticancer drugs such as L-DOX. Moreover, HIV PIs possess an inhibitory effect on P-gp function that may improve DOX sensitivity in KS spindle cells.