ABSTRACT:
The over-expression of the multidrug resistant (MDR-1) mRNA, encoding P-glycoprotein (PgP), has been implicated as playing a role in multidrug resistance in numerous human malignancies and chloroquine-resistant Plasodium falciparum infections. Recently, HIV-1 protease inhibitors have been described to be substrates of PgP. To test the hypothesis that over-expression of MDR-1 can be observed in viv o in HIV-1-infected patients treated with a protease inhibitor, we quantified PgP expression and performed functional tests of PgP activity. The sample set consisted of 18 HIV-1-infected patients, 15 males and three females with a median age of 42 years. The median CD4 count was 164 cells/mm3 (range 3-847) and the median HIV-1 RNA level was 200 copies/ml (range 200-512671). All patients were treated with a combination of reverse transcriptase inhibitors plus one or tow protease inhibitors (median duration was 33 months, range was 4-37).
Among these patients, 10 had an HIV-1 RNA level <200 copies/ml, and eight had an HIV-1 RNA level >200 copies/ml. Among these patients with virological failure, all had one or more mutations in the protease gene. Plasma protease concentrations were in the range of therapeutic values. The expression and function of PgP were performed on peripheral blood mononuclear cells with selected cells by UIC2, FITC, CD4 PE and CD14 PC5 antibodies. Quantification of PgP expression was measured using flow cytometry and expressed as a continuous D-value function using the Kolmorogov-Smirnov test. PgP was found in the CD4 cells of 6/18 patients (33%). In these six patients, functional assays were performed using flow cytometry (rhodamine 123 was the substrate alone, or in the presence of the PgP-modulator cyclosporin A. Functional tests of PgP activity were positive in the CD4 cells of all patients who expressed PgP (100%). In conclusion, in HIV-1-infected patients, treated with a combination containing a protease inhibitor, the expression and function of PgP can be increased. The role of PgP in patients treated with a protease inhibitor needs to be clarified in further studies.
