HIV-protease inhibitors contribute to P-glycoprotein efflux function defect in peripheral blood lymphocytes from HIV-positive patients receiving HAART.
P-glycoprotein (P-gp) has been found expressed in normal human cells, such as bone marrow and peripheral blood cells. The aim of this study was to investigate whether HIV-protease inhibitors (HIV-PIs) interact with P-gp efflux function in normal human peripheral blood lymphocytes (PBLs) and CD34+ progenitor cells. Moreover, we analyzed the in vivo effect of HIV-PIs on P-gp function in PBLs from HIV-infected patients receiving highly active antiretroviral therapy (HAART). We found that HIV-PIs (i.e., ritonavir, saquinavir, nelfinavir and indinavir) interfere with P-gp function in normal PBLs as demonstrated by the reduced efflux of rhodamine 123 (Rh123). This effect was dose-dependent and suggested the following hierarchy: ritonavir > saquinavir > nelfinavir > indinavir. We further analyzed the effect of HIV-PIs on the P-gp function in specific PBLs subsets. Our results show an HIV-PI-induced inhibition of P-gp function in CD4+ and CD8+ T cell subsets, mostly caused by the effect on the naive compartment of both CD4+ and CD8+ T cells. The same inhibitory effect was found in CD34+ hematopoietic progenitor cells. With respect to the in vivo evaluation of P-gp function in PBLs from HIV-infected patients, we found reduced levels of Rh123 efflux that reached the lowest value in AIDS patients receiving HAART. We concluded that HIV-PIs interfere with P-gp function in major cellular targets for HIV infection, such as CD4+ T cells and CD34+ progenitor cells. This ability may contribute to P-gp efflux function defect found in HIV-infected patients and suggests that drug interaction studies are crucial to an overall understanding of the effects of this important group of drugs.
Lucia
M B
MB
Departments of Infectious Diseases and Hematology, Catholic University, Rome, Italy.
Rutella
S
S
Leone
G
G
Vella
S
S
Cauda
R
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D018952:Antigens, CD34 / Q000378:metabolism; D023241:Antiretroviral Therapy, Highly Active; D001693:Biological Transport, Active / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D019469:Indinavir / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D019888:Nelfinavir / Q000494:pharmacology; D012367:RNA, Viral / Q000097:blood; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D019438:Ritonavir / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018952:Antigens, CD34; D005456:Fluorescent Dyes; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D020112:Rhodamine 123; D019469:Indinavir; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir