TY - JOUR
T1 - Antiviral activity of HIV type 1 protease inhibitors nelfinavir and indinavir in vivo is not influenced by P-glycoprotein activity on CD4 + T cells
AU - Sankatsing, Sanjay U.C.
AU - Cornelissen, Marion
AU - Kloosterboer, Nico
AU - Crommentuyn, Kristel M.L.
AU - Bosch, Tessa M.
AU - Mul, Frederik P.
AU - Jurriaans, Suzanne
AU - Huitema, Alwin D.R.
AU - Beijnen, Jos H.
AU - Lange, Joep M.A.
AU - Prins, Jan M.
AU - Schuitemaker, Hanneke
PY - 2007/1
Y1 - 2007/1
N2 - 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-gphigh) or low (P-gplow) P-gp activity. Unspliced HIV-1 RNA and HIV-1 DNA load were determined. For each patient P-gphigh and P-gplow subsets were compared. In patients on a PI-containing regimen, intracellular unspliced HIV-1 RNA was significantly lower in P-gphigh-naive CD4+ cells compared to P-gplow-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-gplow 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.
AB - 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-gphigh) or low (P-gplow) P-gp activity. Unspliced HIV-1 RNA and HIV-1 DNA load were determined. For each patient P-gphigh and P-gplow subsets were compared. In patients on a PI-containing regimen, intracellular unspliced HIV-1 RNA was significantly lower in P-gphigh-naive CD4+ cells compared to P-gplow-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-gplow 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.
UR - http://www.scopus.com/inward/record.url?scp=33846829839&partnerID=8YFLogxK
U2 - 10.1089/aid.2006.0027
DO - 10.1089/aid.2006.0027
M3 - Article
C2 - 17263628
AN - SCOPUS:33846829839
SN - 0889-2229
VL - 23
SP - 19
EP - 27
JO - AIDS Research and Human Retroviruses
JF - AIDS Research and Human Retroviruses
IS - 1
ER -