Antiviral activity of HIV type 1 protease inhibitors nelfinavir and indinavir in vivo is not influenced by P-glycoprotein activity on CD4+ T cells.
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.
Sankatsing
Sanjay U C
SU
International Antiviral Therapy Evaluation Center, Amsterdam, The Netherlands. s.u.sankatsing@amc.uva.nl
Cornelissen
Marion
M
Kloosterboer
Nico
N
Crommentuyn
Kristel M L
KM
Bosch
Tessa M
TM
Mul
Frederik P
FP
Jurriaans
Suzanne
S
Huitema
Alwin D R
AD
Beijnen
Jos H
JH
Lange
Joep M A
JM
Prins
Jan M
JM
Schuitemaker
Hanneke
H
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004279:DNA, Viral; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D019469:Indinavir; D019888:Nelfinavir