Background:  We have previously demonstrated that expression of P-glycoprotein (P-gp) and CXCR4 (X4) positively correlate on the surface of peripheral blood mononuclear cells (PBMC) from healthy volunteers. Further, expression of these proteins positively correlates with the antiviral IC₅₀ of saquinavir. These relationships may be important in determining disease progression and treatment outcome in HIV⁺ individuals. There is evidence however, that infection with HIV can affect expression levels of both of these proteins. The aim of this study was to assess whether relationships between X4 and the membrane transporters P-gp, multidrug resistance–associated protein-1 (MRP1) and breast cancer–resistance protein (BCRP) exist in HIV⁺ individuals and more specifically within the CD4⁺ cell population, a major site of HIV replication.

Methods:  Subjects (n = 93) had a median CD4 count of 343 cells/mm³ (range 8 to 1318), diverse treatment histories (treatment naïve n = 40, experienced n = 53) and a median detectable viral load of 4760. Of 93 patients, 34 had undetectable viral load. P-gp, BCRP, and MRP1 were quantified on PBMC by flow cytometry and cells were co-stained for CD4. Correlations between protein expression were analyzed by Spearmans rank correlation.

Results:  A positive correlation was observed between P-gp and X4 expression in total PBMC from HIV⁺ individuals (R = 0.53, p < 0.0001, 95% CI = 0.28 to 0.80). This correlation was also observed in the CD4⁺ population (R = 0.30, p = 0.003, 95% CI = 0.37 to 0.67). MRP1 expression correlated to that of X4 in total PBMC (R = 0.41; p = 0.04; 95% CI = 0.01 to 0.69), as well as P-gp (R = 0.25, p = 0.02, 95% CI = 0.04 to 0.43). Expression of BCRP correlated with P-gp (R = 0.25, p = 0.03, 95% CI 0.03 to 0.44) but not X4.

Conclusions:  Despite the reported down regulation of X4 in HIV⁺ PBMC, and possible modulation of transporter expression, we have demonstrated a strong correlation between P-gp and X4 on PBMC isolated from HIV⁺ individuals. Importantly, this relationship is also present in the CD4⁺ cell subset. Further, we report a correlation between X4 and MRP1. Such correlations in the context of HIV infection may have implications for viral pathogenesis, viral resistance and therapy success. High expression of X4 may promote the evolution of the more pathogenic X4 strains of HIV and, if coupled with high transporter expression, decreased intracellular drug penetration may make these viruses harder to control.

Keywords: HIV; multidrug resistance transporters; chemokine receptors