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Understanding the Role of Cyclophilins in HCV Replication and the Mechanisms of Action of Cyclophilin InhibitorsCyclophilin inhibitors (CypI) have demonstrated great potential for the treatment of HCV patients as IFN-free regimens. ABBOTT, BIORAD, CDS, CTK, DIAGMEX, HYCEL, INSTANT-VIEW, MEDICA, MEXLAB, MBM, PH, POINTE SCIENTIFIC, RANDOX, ROCHE, SPINREACT, STRECK, THERMO ALKO, ENTRE OTRAS. Ofreciendo servicio, consumibles y accesorios para el total funcionamiento de sus equipos con certeza y exactitud. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics.
Despite intense academic and pharmaceutical research, their mechanisms of antiviral action remain poorly understood. It is important to emphasize that very recent findings suggest that the NS5B polymerase as well as NS2 could represent additional indirect ligands for CypA. We and others demonstrated that the host peptidyl-prolyl isomerase protein - cyclophilin A (CypA) - is absolutely necessary for HCV replication and represents the prime intracellular target for CypI. Therefore, at this stage one cannot exclude the possibility that Cyp inhibitors block HCV replication by interfering with several steps of the HCV replication cycle as suggested in the model below (Figure 6). We also obtained several lines of evidence that the HCV protein NS5A serves as the main viral ligand for CypA. A main goal in the laboratory is to understand why HCV exploits CypA to replicate in humans, to understand at a molecular level how CypA assist HCV, and to unravel the mechanisms of action of this novel class of promising anti-HCV agents - the Cyps inhibitors.

To confirm induction of HSC apoptosis by NK cells, we repeated these experiments using either TUNEL assays (d) or analysis of cleaved PARP (e) instead of studying active caspase-3 to detect HSC apoptosis. Thus, there is a direct correlation between preventing NS5A-CypA interactions and inhibiting HCV replication. One attractive possibility is that CypA regulates the formation of a functional HCV RNA complex (RC). In this model, CypA, by interacting with NS5A, dictates the optimal composition of the HCV RNA complex in specific viral and host components, which are absolutely required for HCV RNA synthesis (Model 1). Indeed, we found that CypI exert no inhibitory effect when added to isolated HCV RCs, suggesting that CypA inhibition does not affect HCV RNA replication after RC formation. We thus postulated that CypA plays a role earlier in HCV replication, such as on the formation of mini-organelles facilitating RNA replication. Supporting this hypothesis, we found by electron microscopy (EM) that HCV-infected, but not uninfected cells contain high numbers of double membrane vesicles (DMVs). Importantly, we found that CypI prevent the formation HCV- as well as NS5A-mediated DMVS formation.
The two proposed models are not mutually exclusive since CypA may play consecutive and distinct roles in the establishment of an enzymatically functional HCV RNA complex. The CypA-NS5A interaction is conserved among genotypes and is interrupted by Cyp inhibitors.

Inhibiting HCV polyprotein processing: C-terminal NS5A mutations, which confer Cyp inhibitor resistance, slow down the processing of JFH-1 polyprotein precursor. In this model, CypA neutralization by Cyp inhibitors would interfere with RC formation (Model I).
It remains to be demonstrated that CypA affects the processing of polyproteins of other genotypes.
Preventing CypA recruitment into RC: CypA locates in a protease-resistant compartment similar to that where HCV replicates. If this model is correct (Model II), it would suggest that HCV exploits a protected compartment enriched with CypA to initiate RC formation.
Since NS5A also plays an essential role in HCV assembly, one could envision that CypA neutralization by Cyp inhibitors could also interfere with particle release (Model IV). Neutralizing NS2 activities: NS2 contributes to RNA replication by cleaving off itself from NS3. One could envision that CypA-NS2 contacts trigger the proper folding of NS2 and enhance NS2 activities.

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