Virus-drug interactions--molecular insight into immunosuppression and HCV

Abstract

Liver transplantation is an effective treatment for end-stage liver disease that is attributable to chronic HCV infection. However, long-term outcomes are compromised by universal virological recurrence in the graft. Reinfection that occurs after transplantation has increased resistance to current interferon-based antiviral therapy and often leads to accelerated development of cirrhosis. Important risk factors for severe HCV recurrence are linked to immunosuppression. Owing to the lack of good randomized, controlled trials, the optimal choice of immunosuppressants is still debated. By contrast, much progress has been made in the understanding of HCV biology and the antiviral action of interferons. These new insights have greatly expanded our knowledge of the molecular interplay between HCV and immunosuppressive drugs. In this article, we explore the effect of different immunosuppressants on the complex cellular events involved in HCV infection and interferon signalling. Potential implications for clinical practice and future drug development are discussed.

Figure 1. Mechanisms of action of GCs and CaN inhibitors.

Mechanisms are shown in a | leukocytes and b | hepatocytes. GCs diffuse into cells and bind to the GR. The GC–GR complex translocates to the nucleus to regulate gene expression. The GC–GR complex interacts with GRE promoter elements and suppresses the expression of inflammatory genes and cytokines, such as IL-2, thereby inhibiting T-cell proliferation. Steroids facilitate HCV entry in hepatocytes by upregulating gene expression of two essential HCV entry receptors—occludin and scavenger receptor class B type I—conceivably via positive GRE promoter elements. GR and type I interferon signalling share the coregulator GRIP1. Ciclosporin A binds to cyclophilin, while tacrolimus binds to FK506-binding protein, forming a complex to block calcineurin. Suppression of the serine/threonine phosphatase activity of calcineurin results in inhibition of TCR/CD3 induced T-cell proliferation by blockage of IL-2 production. Ciclosporin A binds to cyclophilin A and cyclophilin B to block the function of NS2, NS5A or NS5B to affect viral replication in hepatocytes. Protein phosphorylation induced by signal transduction is indicated by P in orange. Abbreviations: AP1, activator protein 1; CaN, calcineurin; CsA, ciclosporin A; CyP, cyclophilin; FKPB, FK506-binding protein; GC, glucocorticosteroid; GR, cytoplasmic receptor; GRE, glucocorticoid response element; GRIP1, glucocorticoid receptor-interacting protein 1, IRF9, interferon regulatory factor 9; ISG, interferon-stimulated gene; ISRE, interferon stimulated response element; JAK1, Janus kinase 1; LD, lipid droplet; NF-ATc, nuclear factor of activated T cells; NFκB, nuclear factor κB; NS, nonstructural protein; SR-BI, scavenger receptor class B type I; STAT, signal transducers and activators of transcription; Tac, tacrolimus; TCR, T-cell receptor; TYK2, nonreceptor tyrosine-protein kinase.

Figure 2. Mechanisms of action of mycophenolic acid and rapamycin.

Mechanisms shown in a | leukocytes and b | hepatocytes. The uptake of MPA by cells involves organic anion transporting polypeptides and probably other transporters as well. MPA is an uncompetitive inhibitor of IMPDH and results in the inhibition of de novo nucleotide biosynthesis. Insufficient intracellular levels of guanosine nucleotide pools result in a defect of nominal DNA duplication that is thought to be the immunosuppressive mechanism of MPA. In hepatocytes, persistent attenuation of nucleotide biosynthesis by MPA partially contributes to the inhibition of HCV replication. In addition to this IMPDH-dependent antiviral pathway, MPA also conveys a rapid antiviral effect mediated by induction of the expression of interferon-stimulated genes. Through an unknown mechanism, MPA directly potentiates the activity of the ISRE promoter element both in the presence or absence of IFN-α stimulation. Rapamycin engages the cytosolic protein FKBP12 to form a complex. This complex inhibits the mTOR pathway by directly binding to the mTORC1, resulting in blockage of cell cycle progression at the G1 to S phase and thereby causing inhibition of T-cell proliferation. Rapamycin is a potent autophagy inducer, which facilitates HCV infection. The mTOR pathway directly interacts with interferon-activated JAK–STAT signalling. Protein phosphorylation induced by signal transduction is indicated by P in orange. Abbreviations: FKBP12, FK506 binding protein 12; GMP, guanosine monophosphate; IMP, inosine monophosphate; IMPDH, inosine monophosphate dehydrogenase; IRF9, interferon regulatory factor 9; ISG, interferon-stimulated gene; ISRE, interferon stimulated response element; JAK1, Janus kinase 1; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin; mTORC, mammalian target of rapamycin complex; STAT, signal transducers and activators of transcription; TYK2, nonreceptor tyrosine-protein kinase.