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Sixth International CongressDrug Therapy in HIV Infection17-21 November, 2002
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[ABSTRACT:] Increased expression of the efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) has been suggested as a potential mechanism for decreased protease inhibitor (PI) availability at certain intracellular sites, providing sanctuary for HIV. Virus primarily targets cells that express the CD4 membrane antigen, therefore P-gp expression on these cells may impact PI efficacy. In addition, CD8 cells which are infectable in vitro, are also important in vivo to aid the immune response. This study investigates a) the effect of PIs in vitro on P-gp expression in CD4 and CD8 lymphocyte subpopulations obtained from healthy volunteers and b) P-gp and MRP1 expression in PBMCs from HIV-infected subjects on regimens with and without PIs.
Initially, peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers (n=15) and basal P-gp expression assessed in CD4, CD8 and CD56 lymphocyte subpopulations. Further PBMC samples (n=12) were isolated and incubated (72h) with 10µM saquinavir (SQV), ritonavir (RTV), nelfinavir (NFV), indinavir (IDV), amprenavir (APV), lopinavir (LPV) and dimethyl sulfoxide (DMSO) control. In the second part of the study PBMCs were isolated from HIV patients (viral load <50 copies/ml) on combination antiretroviral therapy, either containing a single protease inhibitor (RTV n=6, SQV n=7, IDV n=7, NFV n=6, LPV n=10) or containing no protease inhibitor (n=9). Expression of P-gp and MRP1 was analysed by dual colour flow cytometry. Statistical differences between drug groups were analysed by Kruskal-Wallis multiple comparison.
Differential basal P-gp expression in CD4, CD8 and CD56 lymphocyte subsets was observed with a significant hierarchy of CD56>CD8>CD4. Although there was a trend to increased P-gp expression (in vitro) in the total PBMC population, CD4 and CD8 subpopulations on incubation with some PIs, no statistical significance was observed. There was no alteration of P-gp expression on administration of any sole PI regime in vivo. Similarly, PI administration had no effect on the expression of MRP1 in this patient cohort.
Although it has previously been shown that higher concentrations of PIs (100µM) significantly induce P-gp expression in vitro, a concentration of 10µM (more closely related to plasma level) had limited inducing effect. The in vivo data were consistent with this finding. Factors other than PI induction are clearly important in the inter-individual variability in transporter expression in PBMCs.Presenting author: Jennifer Ford
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1 University of Liverpool, Liverpool, United Kingdom
2002-11-17
PL8-3b
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