Cyclophilins and Their Roles in Hepatitis C Virus and Flavivirus Infections: Perspectives for Novel Antiviral Approaches

Abstract

Cyclophilins are cellular peptidyl-prolyl isomerases that play an important role in viral infections, with demonstrated roles in the replication of hepatitis C virus (HCV) and other viruses in the Flaviviridae family, such as dengue virus (DENV) and yellow fever virus (YFV). Here, we discuss the roles of cyclophilins in HCV infection and provide a comprehensive overview of the mechanisms underlying the requirement for cyclophilins during HCV replication. Notably, cyclophilin inhibitor therapy has been demonstrated to be effective in reducing HCV replication in chronically infected patients. While the roles of cyclophilins are relatively well-understood for HCV infection, cyclophilins are more recently emerging as host factors for flavivirus infection as well, providing potential new therapeutic avenues for these viral infections which currently lack antiviral therapies. However, further studies are required to elucidate the roles of cyclophilins in flavivirus replication. Here, we review the current knowledge of the role of cyclophilins in HCV infection to provide a conceptual framework to understand how cyclophilins may contribute to other viral infections, such as DENV and YFV. Improved understanding of the roles of cyclophilins in viral infection may open perspectives for the development of cyclophilin inhibitors as effective antiviral therapeutics for HCV and related viruses.

Keywords: antiviral therapy; cyclophilins; flaviviruses; hepatitis C virus; virus-host interactions.

Figure 1

Immunosuppressive effect of CsA. (A) T-cell activation depends on the dephosphorylation of the transcription factor nuclear factor of activated T-cells (NFAT). Calcineurin catalyzes dephosphorylation of NFAT, enabling its nuclear translocation. (B) The CypA inhibitor, CsA, binds to CypA, enabling the CypA-CsA complex to bind to and inhibit calcineurin, thus preventing dephosphorylation and nuclear translocation of NFAT.

Figure 2

Crystal structure of CypA. PPI active site residues R55 (pink), F60 (violet) and H126 (cyan) are shown. The structure was rendered in PyMOL (PDB: 4IPZ).

Figure 3

Suggested roles of cyclophilins during HCV infection. Cyps have been shown to have roles in several post-entry steps of HCV infection. (1) Formation of the CypA–NS5A complex inhibits the function of PKR, preventing activation of PKR-related antiviral immune responses. (2) The CypA–NS5A complex binds to the RdRp NS5B, enhancing replication of viral RNA. CypB also acts as a cofactor of NS5B, facilitating viral RNA replication. (3) CypA is required for formation of the HCV replication organelle and for optimal lipid droplet formation and lipid trafficking, supporting viral assembly and egress.

Figure 4

The role of cyclophilins in flavivirus infection. Treatment with CsA or other CypI inhibits DENV, YFV, WNV, ZIKV and JEV infection, although identification of the specific mechanisms and relevant Cyp(s) require further investigation. WNV NS5 RdRp interacts with CypA, which may contribute to viral RNA replication. Interactions between JEV NS4A and CypB, and YFV NS4B and CypA, may support viral replication by contributing to replication organelle formation.

Figure 5

Chemical structures of CypI. CsA (left) and Sanglifehrin A (right) are shown.