476 HIV-1 Infection Is Associated with Changes in Drug Transporter Gene Expression In Vivo MP De Pasquale*, T. Hulgan, L. Sutton, W.F Carlisle, H. Erdem, M. Rueff, C. McGowan, R. Kim, J.P. Donahue, D. W. Haas, R.T. D’Aquila Vanderbilt Univ Med Ctr, Nashville, TN
Background: Drug transporters P-glycoprotein (Pgp) and multi-drug resistance-associated protein 4 (MRP4) efflux protease inhibitors (PI) and nucleoside RT inhibitors (NRTI), respectively. This cross sectional study investigated whether Pgp or MRP4 expression in peripheral blood mononuclear cells (PBMC) in vivo varied based on HIV-1 infection or antiretroviral drug exposure. Such modulation may contribute to pathogenesis, or to variability in antiretroviral drug responses not explained by virus resistance.
Methods: RNA was extracted from Ficoll-gradient separated PBMC of 10 HIV-1 seronegative and 57 HIV-1 infected adults. Pgp and MRP4 transcripts were quantified by real-time RT-PCR, normalized to GAPDH RNA. Wilcoxon Rank Sum, Spearman correlation, Pearson Chi-square, and Fisher exact tests were used, as appropriate.
Results: Levels of Pgp RNA were significantly lower in HIV-infected subjects than in uninfected subjects (Mean: 3.4 vs 9.4 copies/pg, respectively; p = 0.0002). Antiretroviral therapy (ART) was currently prescribed to 46 (81%) of the HIV+ subjects; this included a PI in 25 (54%), an NNRTI in 9 (20%), and only NRTIs in 15 (33%). Among the HIV+ subjects, those on ART had significantly higher Pgp RNA levels than the untreated (Mean: 3.7 vs 2.4 copies/pg, respectively; p = 0.046). However, level of Pgp RNA was not associated with current use of a specific ART drug class (p = 0.15). MRP4 RNA levels did not differ between the HIV+ and HIV- subjects, or by ART among the HIV+s. There was a non-significant trend for NRTI-only ART to be more common among subjects with MRP4 levels in the highest quartile. Pgp and MRP4 RNA levels were correlated in HIV+ subjects (Spearman’s rho = 0.37; p = 0.005).
Conclusions: These results suggest that HIV infection is associated with significantly decreased PBMC Pgp RNA levels and that ART is associated with higher levels of Pgp expression. In contrast, MRP4 RNA levels did not differ significantly by HIV infection or ART. We hypothesize that HIV replication may cause a decrease in Pgp gene expression, and that ART may reverse this effect. More data are required to determine whether exposure to specific drugs predict Pgp or MRP4 RNA levels. Relationships between levels of Pgp RNA and Pgp efflux function are also under investigation.