Abnormal Expression of a 170-Kilodalton P-Glycoprotein Encoded byMDR1Gene, a Metabolically Active Efflux Pump, in CD4+and CD8+T Cells from Patients with Human Immunodeficiency Virus Type 1 Infection

Abstract

Peripheral blood CD4⁺ and CD8⁺ T cells from 16 patients with HIV-1 infection, 8 each with CD4⁺ T cell counts of >200/mm³ (group I) and with CD4⁺ T cell counts of 3 (group II), and 8 age- and sex-matched controls, were examined for the expression of P-glycoprotein (P-gp), a 170-kDa phosphoglycoprotein encoded by the MDR1 gene, using dual-color flow cytometric analysis. The function of P-glycoprotein was assessed by the accumulation of rhodamine-123 (Rh123) dye in the presence or absence of cyclosporin A (which inhibits Rh123 efflux). A significantly increased proportion of CD4⁺ T cells from patients with HIV-1 infection expressed P-glycoprotein as compared to controls, resulting in a significantly increased ratio of the proportions of CD4⁺P-gp⁺/CD8⁺P-gp⁺ cells. The ratio of CD4⁺P-gp⁺/CD8⁺P-gp⁺ in group II patients was significantly higher (p = 0.02) than in group I patients, suggesting a progressive increase in P-gp expression with the advancement of HIV-1 infection. The proportions of CD4⁺P-gp⁺ and CD8⁺P-gp⁺ T cells did not differ significantly between those who received AZT and those who were not treated with AZT. Contrary to expectation, both CD4⁺ and CD8⁺ T cells from patients accumulated significantly more Rh123 as compared to controls. Furthermore, cyclosporin A failed to increase intracellular accumulation of Rh123 in CD4⁺ and CD8⁺ T cells from patients. These data suggest a functionally defective P-gp expression in HIV-1 infection that appears to increase with the progression of HIV-1 infection. A study of a large number of patients with HIV-1 infection is needed to determine the effects of opportunistic infection and antiretroviral therapy on the expression of P-gp and to determine whether the expression of P-gp could serve as another surrogate marker for the progression of HIV-1 infection.