HIV glycoprotein gp120 enhances mesenchymal stem cell migration by upregulating CXCR4 expression.

BACKGROUND: HIV infection and/or the direct pathogenic effects of circulating HIV proteins impairs the physiological function of mesenchymal stem cells (MSCs), and contribute to the pathogenesis of age-related clinical comorbidities in people living with HIV. The SDF-1/CXCR4 pathway is vital for modulating MSC proliferation, migration and differentiation. HIV glycoprotein gp120 inhibits SDF-1 induced chemotaxis by downregulating the expression and function of CXCR4 in monocytes, B and T cells. The influence of gp120 on CXCR4 expression and migration in MSCs is unknown. METHODS: We investigated CXCR4 expression and SDF-1/CXCR4-mediated MSC migration in response to gp120, and its effect on downstream signaling pathways: focal adhesion kinase (FAK)/Paxillin and extracellular signal-regulated kinase (ERK). RESULTS: Gp120 upregulated MSC CXCR4 expression. This potentiated the effects of SDF-1 in inducing chemotaxis; FAK/Paxillin and ERK pathways were over-activated, thereby facilitating actin stress fiber reorganization. CXCR4 blockage or depletion abrogated the observed effects. CONCLUSION: Gp120 from both T- and M- tropic HIV strains upregulated CXCR4 expression in MSCs, resulting in enhanced MSC chemotaxis in response to SDF-1. GENERAL SIGNIFICANCE: HIV infection and its proteins are known to disrupt physiological differentiation of MSC; increased gp120-driven migration amplifies the total MSC population destined for ineffective and inappropriate differentiation, thus contributing to the pathogenesis of HIV-related comorbidities. Additionally, given that MSCs are permissive to HIV infection, initial cellular priming by gp120 results in increased expression of CXCR4 and could lead to co-receptor switching and cell tropism changes in chronic HIV infection and may have implications against CCR5-knockout based HIV cure strategies.

Unexpected drug-drug interactions in human immunodeficiency virus (HIV) therapy: induction of UGT1A1 and bile efflux transporters by Efavirenz.

INTRODUCTION: Efavirenz is an inducer of drug metabolism enzymes. We studied the effect of efavirenz and ritonavir-boosted darunavir on serum unconjugated and conjugated bilirubin, as probes for UGT1A1 and bile transporters. MATERIALS AND METHODS: Healthy volunteers were enrolled in a clinical trial. There were 3 periods: Period 1, 10 days of darunavir 900 mg with ritonavir 100 mg once daily; Period 2, 14 days of efavirenz 600 mg with darunavir/ritonavir once daily; and Period 3, 14 days of efavirenz 600 mg once daily. Serum bilirubin (conjugated and unconjugated) concentrations were obtained at baseline, at the end of each phase and at exit. RESULTS: We recruited 7 males and 5 females. One subject developed grade 3 hepatitis on efavirenz and was excluded. Mean serum unconjugated bilirubin concentrations were 6.09 µmol/L (95% confidence interval [CI], 4.99 to 7.19) at baseline, 5.82 (95% CI, 4.88 to 6.76) after darunavir/ritonavir, 4.00 (95% CI, 2.92 to 5.08) after darunavir/ritonavir with efavirenz, 3.55 (95% CI, 2.58 to 4.51) after efavirenz alone and 5.27 (95% CI, 3.10 to 7.44) at exit (P <0.01 for the efavirenz phases). Mean serum conjugated bilirubin concentrations were 3.55 µmol/L (95% CI, 2.73 to 4.36) at baseline, 3.73 (95% CI, 2.77 to 4.68) after darunavir/ritonavir, 2.91 (95% CI, 2.04 to 3.78) after darunavir/ritonavir with efavirenz, 2.64 (95% CI, 1.95 to 3.33) after efavirenz alone and 3.55 (95% CI, 2.19 to 4.90) at exit (P <0.05 for the efavirenz phases). CONCLUSION: Efavirenz decreased unconjugated bilirubin by 42%, suggesting UGT1A1 induction. Efavirenz also decreased conjugated bilirubin by 26%, suggesting induction of bile efflux transporters. Ritonavir-boosted darunavir had no effect on bilirubin concentrations. These results indicate that efavirenz may reduce concentrations of drugs or endogenous substances metabolized by UGT1A1 or excreted by bile efflux transporters.