Abstract
The mechanisms of action by which cyclophilin inhibitors (CypI) interfere with the HCV life cycle remain poorly understood. We reported that CypI and NS5A inhibitors (NS5Ai), but not other classes of anti-HCV agents, prevent assembly of double membrane vesicles (DMVs), which protect replication complexes. We demonstrated that both NS5A and the isomerase cyclophilin A (CypA) are required for DMV formation. Here, we examined whether CypI mediate an additional antiviral effect that could further explain the high efficacy of CypI. We identified a unique action of CypI. CypI remodel the organization of the endoplasmic reticulum (ER) of HCV-infected cells, but not of uninfected cells. This effect is specific since it was not observed for other classes of anti-HCV agents including NS5Ai, and has no effect on the viability of CypI-treated cells. Since ER serves as platform for the establishment of HCV replication complexes, we asked whether the ER reorganization by CypI would prevent cells from being newly infected. Remarkably, CypI-treated HCV-pre-infected cells remain totally impervious to a reinfection, suggesting that the CypI-mediated ER reorganization prevents a reinfection. This block is not due to residual CypI since CypI-resistant HCV variants also fail to infect these cells. The ER reorganization by CypI is rapid and reversible. This study provides the first evidence that CypI trigger a unique ER reorganization of infected cells, rendering cells transiently impervious to a reinfection. This study further suggests that the HCV-induced ER rearrangement represents a key target for the development of new therapies.
Highlights
More than 200 million people are affected by chronic hepatitis C, which is a leading cause of acute and chronic liver diseases, and approximately 4 million new HCV infections occur every year [1,2]
In contrast to the NS5Bi, sofosbuvir, and the NS5A inhibitors (NS5Ai), ledispavir, that do not significantly influence the endoplasmic reticulum (ER) structure of HCV-infected cells, we found that the cyclophilin inhibitors (CypI), ALV, markedly alters the structure of the ER of infected cells (Fig 1A)
We recently reported that NS5A and cyclophilin A (CypA), via its ligand binding or peptidyl cis-trans isomerase activity, act in concert to create these protective membranous organelles [31]
Summary
More than 200 million people are affected by chronic hepatitis C, which is a leading cause of acute and chronic liver diseases, and approximately 4 million new HCV infections occur every year [1,2]. Several direct-acting antiviral (DAAs) such as NS3 (NS3i), NS5A (NS5Ai) and NS5B (NS5Bi) inhibitors have been FDA-approved and have shown high efficacy in patients, but the cost of these IFN-free DAA regimens is significantly expensive [4]. One option to decrease the cost of these DAA treatments is to reduce the time of drug administration, while still providing efficacy. Because current IFN-free DAA treatments mainly entail identical classes of inhibitors—NS3i, NS5Ai and NS5Bi—it is expected that their costs will be elevated at least for a few years and will offer comparable degrees of efficacy. Incorporating drugs with distinct mechanisms of action (MoA) into IFN-free DAA regimens could offer an opportunity for reducing the time of DAA treatments and prevent the possibility of the development of drug resistance
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