During the last few years, highly active antiretroviral therapy has considerably reduced human immunodeficiency virus (HIV) disease progression (11). However, the treatment outcome is not always satisfactory (7). This can depend on different virological, immunological, behavioral, or pharmacological factors (5). In the framework of aspects, the interaction between P-glycoprotein (P-gp) and antiretroviral drugs has been evidenced (8, 13, 15). P-gp is a transmembrane phosphoglycoprotein belonging to the ATP-binding cassette superfamily that is able to transport several substrates through the cell membrane acting as a cationic pump (2, 3, 4, 6, 9, 14). Specifically, studies on protease inhibitors (PI) have evidenced that the transporter activity of P-gp may contribute to the reduced bioavailability of these drugs, which can act as substrates for P-gp (4, 15, 16). However, the influence of HIV infection on P-gp expression is still a matter of debate (1, 9), and as yet, no data are available on the effects of highly active antiretroviral therapy on its expression.
The intensity of P-gp expression on peripheral blood mononuclear cells (PBMC) from healthy donors is 1.8 ± 0.5, as indicated by an intensity index described below (see footnote to Table 1). Recently, it has been reported that P-gp expression on PBMC was reduced in HIV-positive (HIV+) persons when compared with that found in healthy donors (10). Using the same approach, we analyzed the influence of antiretroviral treatment and that of viral and immunological parameters on P-gp expression on PBMC from 18 HIV+ persons. We defined three groups (Table 1): (i) HIV+ patients naive for antiretroviral therapy (n = 5); (ii) HIV+ patients with a successful response to the therapy (n = 8); and (iii) HIV+ patients with failing virological response to the therapy (n = 5). Treatment protocols of all patients are reported in Table 1.
In this pilot study, the expression of P-gp in total PBMC, CD4+ T lymphocytes, and CD14+ monocytes from naive, responder, and nonresponder patients was analyzed by flow cytometry. The intensity of P-gp expression on total PBMC of HIV+ patients was very low (0.99 ± 0.12), confirming previous observations (10). Further analysis among CD4+ T cells and CD14+ monocytes showed a higher intensity of P-gp expression on CD14+ monocytes than in CD4+ T lymphocytes (2.2 ± 1.3 versus 1.04 ± 0.16 [P < 0.05]). To asses whether the lack of virological response to the therapy treatment may be correlated with a different intensity of P-gp expression on the cell surface, we compared P-gp expression in the three groups of HIV+ patients described above (naive, responder, and nonresponder). No differences among these groups were observed in P-gp expression on total PBMC (naive, 1.04 ± 0.02; responder, 1.00 ± 0.02; and nonresponder, 0.92 ± 0.10), CD4+ T lymphocytes (naive, 1.14 ± 0.05; responder, 1.02 ± 0.04; and nonresponder, 0.98 ± 0.11), and CD14+ monocytes (naive, 2.67 ± 0.90; responder, 2.16 ± 0.39; and nonresponder, 1.95 ± 0.36). The frequency of P-gp-positive cells was independent of both the viremia levels and the T-cell count, and no difference between patients treated with PI and patients naive for PI treatment was observed. Altogether, these observation indicate that differences in P-gp levels did not appear to determine virological responses to antiretroviral therapy.
TABLE 1. Analysis of clinical parameters and P-gp expression in total PBMC, CD4+ T lymphocytes, and CD14+ monocytes from HIV+ patientsa
- Copyright © 2003 American Society for Microbiology
REFERENCES
- 1.↵
Andreana, A., S. Aggarwal, S. Gollapudi, D. Wien, T. Tsuruo, and S. Gupta.
1996. Abnormal expression of a 170-kilodalton P-glycoprotein encoded by MDR1 gene, a metabolically active efflux pump, in CD4+ and CD8+ T cells from patients with human immunodeficiency virus type 1 infection. AIDS Res. Hum. Retrovir.12:1457-1462.
- 2.↵
Antonelli, G., O. Turriziani, M. Cianfriglia, E. Riva, G. Dong, A. Fattorossi, and F. Dianzani.
1992. Resistance of HIV-1 to AZT might also involve the cellular expression of multidrug resistance P-glycoprotein. AIDS Res. Hum. Retrovir.8:1839-1844.
- 3.↵
Coon, J. S., Y. Z. Wang, S. D. Bines, P. N. Markham, A. S. Chong, and H. M. Gebel.
1991. Multidrug resistance activity in human lymphocytes. Hum. Immunol.32:134-140.
- 4.↵
Drach, D., S. Zhao, J. Drach, R. Mahadevia, C. Gattringer, H. Huber, and M. Andreeff.
1992. Subpopulations of normal peripheral blood and bone marrow cells express a functional multidrug resistant phenotype. Blood80:2729-2734.
- 5.↵
Fletcher, C. V.
1999. Pharmacologic considerations for therapeutic success with antiretroviral agents. Ann. Pharmacother.33:989-995.
- 6.↵
Gupta, S., C. H. Kim, T. Tsuruo, and S. Gollapudi.
1992. Preferential expression and activity of multidrug resistance gene 1 product (P-glycoprotein), a functionally active efflux pump, in human CD8+ T cells: a role in cytotoxic effector function. J. Clin. Immunol.12:451-458.
- 7.↵
Hirsch, M. S., and D. D. Richman.
2000. The role of genotypic resistance testing in selecting therapy for HIV. JAMA284:1649-1650.
- 8.↵
Kim, R. B., M. F. Fromm, C. Wandel, B. Leake, A. J. Wood, D. M. Roden, and G. R. Wilkinson.
1998. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J. Clin. Investig.101:289-294.
- 9.↵
Lucia, M. B., R. Cauda, A. L. Landay, W. Malorni, G. Donelli, and L. Ortona.
1995. Transmembrane P-glycoprotein (P-gp/P-170) in HIV infection: analysis of lymphocyte surface expression and drug-unrelated function. AIDS Res. Hum. Retrovir.11:893-901.
- 10.↵
Meaden, E. R., P. G. Hoggard, B. Maher, S. H. Khoo, and D. J. Back.
2001. Expression of P-glycoprotein and multidrug resistance-associated protein in healthy volunteers and HIV-infected patients. AIDS Res. Hum. Retrovir.17:1329-1332.
- 11.↵
Palella, F. J., Jr., K. M. Delaney, A. C. Moorman, M. O. Loveless, J. Fuhrer, G. A. Satten, D. J. Aschman, S. D. Holmberg, et al.
1998. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N. Engl. J. Med.338:853-860.
- 12.
Poccia, F., S. Boullier, H. Lecoeur, M. Cochet, Y. Poquet, V. Colizzi, J. J. Fournie, and M. L. Gougeon.
1996. Peripheral V gamma 9/V delta 2 T cell deletion and anergy to nonpeptidic mycobacterial antigens in asymptomatic HIV-1-infected persons. J. Immunol.157:449-461.
- 13.↵
Profit, L., V. A. Eagling, and D. J. Back.
1999. Modulation of P-glycoprotein function in human lymphocytes and Caco-2 cell monolayers by HIV-1 protease inhibitors. AIDS13:1623-1627.
- 14.↵
Schinkel, A. H., E. Wagenaar, C. A. Mol, and L. van Deemter.
1996. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Investig.97:2517-2524.
- 15.↵
Srinivas, R. V., D. Middlemas, P. Flynn, and A. Fridland.
1998. Human immunodeficiency virus protease inhibitors serve as substrates for multidrug transporter proteins MDR1 and MRP1 but retain antiviral efficacy in cell lines expressing these transporters. Antimicrob. Agents Chemother.42:3157-3162.
- 16.↵
Turriziani, O., P. Di Marco, G. Antonelli, and F. Dianzani.
2000. May the drug transporter P glycoprotein affect the antiviral activity of human immunodeficiency virus type 1 proteinase inhibitors? Antimicrob. Agents Chemother.44:473-474.
