Variants in the human PPIA gene render host cells refractory to hepatitis C virus infection by destabilization of the essential host factor cyclophilin A

The hepatitis C virus (HCV), a world-wide leading cause of cirrhosis and liver cancer, utilizes a number of host encoded cofactors to infect and replicate in human hepatocytes. Among these, cyclophilin A (CypA) stands out because it is critical for viral replication and CypA inhibitors like alisporivir are currently the most advanced anti-HCV compounds with a host encoded target in clinical development. Several genetic variants in the PPIA gene encoding CypA have been described but their influence on the course of HCV infection is unknown. The aim of the present study was to determine the prevalence of coding non-synonymous SNP’s in the essential HCV RNA replication factor CypA and to study their impact on HCV replication in vitro, on the anti-viral activity of alisporivir and on the clinical course of HCV infection. We found that three coding non-synonymous single nucleotide polymorphisms (SNP’s) in the PPIA gene render host cells largely non-permissive to HCV infection in vitro. HCV RNA replication was reduced 3–4 log in cells homozygous for the variant allele while viral cell entry add new particle assembly was unaltered. This effect is due to an unusual destabilization of the CypA protein by a single amino acid exchange leading to its rapid degradation. The most frequent HCV non-permissive SNP (N106I) occurred with an allele frequency of 1–3% in different human populations. In line with our in vitro data, in vivo heterozygosity for the N106I allele was not associated with an altered course of disease in chronically HCV infected individuals. Importantly, from a pharmacogenetics perspective, the reported SNP’s are not expected to result in altered sensitivity of replicating HCV to anti-viral CypA inhibitors such as alisporivir.