title: Antiviral activity of HIV type 1 protease inhibitors nelfinavir and indinavir in vivo is not influenced by P-glycoprotein activity on CD4+ T cells.
abstract: P-glycoprotein (P-gp) can compromise the antiretroviral effect of a protease inhibitor (PI)-containing regimen for HIV-1, but can also reduce HIV-1 replication. We studied the net effect of P-gp on the intracellular HIV-1 RNA and DNA load in vivo. CD4(+) T cells were isolated from 27 HIV-1 patients (13 without and 14 with a PI-containing regimen) and subsequently sorted in CD45RO(-) (naive) and CD45RO(+) (memory) subsets with either high (P-gp(high)) or low (P-gp(low)) P-gp activity. Unspliced HIV-1 RNA and HIV-1 DNA load were determined. For each patient P-gp(high) and P-gp(low) subsets were compared. In patients on a PI-containing regimen, intracellular unspliced HIV-1 RNA was significantly lower in P-gp(high)-naive CD4(+) cells compared to P-gp(low)-naive CD4(+) cells (p = 0.04). The same trend was seen in naive CD4(+) cells of treatment naive patients. In both treated and untreated patients HIV-1 DNA levels were significantly lower in P-gp(high) than in P-gp(low) memory CD4(+) cells (p = 0.02 and p = 0.04). High cellular P-gp activity coincided with a reduced intracellular HIV-1 load in vivo, both in therapy-naive and in PI-treated patients. Therefore we conclude that the potential efflux function of P-gp on PIs may be clinically less relevant than the effect of P-gp on intracellular HIV-1 replication.
authors.affiliation: International Antiviral Therapy Evaluation Center, Amsterdam, The Netherlands. s.u.sankatsing@amc.uva.nl
authors.forename: Sanjay U C
authors.initials: SU
authors.lastname: Sankatsing
authors.forename: Marion
authors.initials: M
authors.lastname: Cornelissen
authors.forename: Nico
authors.initials: N
authors.lastname: Kloosterboer
authors.forename: Kristel M L
authors.initials: KM
authors.lastname: Crommentuyn
authors.forename: Tessa M
authors.initials: TM
authors.lastname: Bosch
authors.forename: Frederik P
authors.initials: FP
authors.lastname: Mul
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jurriaans
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Joep M A
authors.initials: JM
authors.lastname: Lange
authors.forename: Jan M
authors.initials: JM
authors.lastname: Prins
authors.forename: Hanneke
authors.initials: H
authors.lastname: Schuitemaker
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D004279:DNA, Viral / Q000097:blood; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1; D006801:Humans; D019469:Indinavir / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008875:Middle Aged; D019888:Nelfinavir / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000097:blood; D019562:Viral Load
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004279:DNA, Viral; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D019469:Indinavir; D019888:Nelfinavir