Background:  PI are known substrates of the efflux transporter P-glycoprotein (P-gp). Recent reports have also suggested a role for P-gp in determining cell susceptibility to HIV with cell lines selected to over-express the protein less susceptible to infection. We have previously described a positive correlation between P-gp and chemokine receptor expression in PBMC. In this study, the functional significance of this relationship has been investigated with regard to viral production and the antiretroviral activity of saquinavir (SQV). 

Methods:  PBL were activated with PHA for 48 hours. P-gp and CXCR4 expression was assessed by flow cytometry. PBL were infected with HIV-IIIB and p24 recovery assessed at day 7 in the presence and absence of the P-gp inhibitor XR9576 and compared using the Wilcoxon signed rank test. SQV IC₅₀ against HIV-IIIB was also calculated. Correlations between IC₅₀, P-gp and CXCR4 expression were assessed using non-parametric linear regression (Spearman’s rank).

Results:  A significant positive correlation was observed between P-gp and CXCR4 expression in activated PBL (Rho = 0.52; p <0.001). Median p24 recovery was 61,210 pg.ml^-1 (range 20040 to 263,400) and weakly correlated to P-gp (Rho = 0.30, p = 0.06) but not CXCR4 expression (Rho = 0.22; p = 0.3). In the presence of XR9576, median p24 recovery was not significantly different (p = 0.12; n = 24). The IC₅₀ of SQV against HIV IIIB in activated PBMC correlated positively with CXCR4 (Rho = 0.57; p = 0.028, see the figure below) and P-gp expression (Rho = 0.71; p = 0.0026, see the figure below) on PBL.

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Conclusions:  In contrast to findings described in cell lines, a weak positive correlation was observed between P-gp expression and p24 recovery following HIV-IIIB infection. p24 recovery was not modulated by inhibition of P-gp suggesting that any effect of P-gp on virus production does not require activity of the protein. Both CXCR4 and P-gp expression correlated to SQV IC₅₀ against HIV-IIIB. Since CXCR4 is not thought to play a role in drug transport, this is likely to be a result of increased P-gp expression resulting in lower intracellular accumulation of drug. Taken together, our findings raise the possibility that cells expressing higher levels of P-gp may not only accumulate less drug but also place a selective pressure in favour of the more pathogenic X4 tropic virus.

Keywords: P-glycoprotein; Chemokine receptors; Antiviral efficacy