Abstract:
BACKGROUND & AIMS:Hepatitis C virus (HCV) uses several host factors to infect and replicate in human hepatocytes. Cyclophilin A (CypA) is required for viral replication, and CypA inhibitors are in development. We investigated the effects of nonsynonymous single nucleotide polymorphisms (SNPs) in the region of peptidyl-prolyl isomerase A (PPIA) that encodes CypA on HCV infection and replication of human hepatocytes. METHODS:We used a combination of virologic, biochemical, and genetic approaches to investigate the effects of PPIA variants on HCV replication in cultured Huh-7.5 cells. We reduced levels of CypA in these cells using small hairpin RNAs (shRNAs). RESULTS:Using shRNAs, we showed that CypA was required for replication of HCV in Huh-7.5 cells and identified 3 SNPs in PPIA that protected cells from HCV entry or replication. Levels of HCV RNA were reduced 3-4 log in cells homozygous for the variant alleles; release of new particles was also reduced, but viral entry was not affected. The effects of the variant alleles were recessive and stronger for preventing replication of full-length HCV genomes than subgenomes. CypA inhibitors prevented replication of residual HCV in hepatocytes. The variants appeared to destabilize the CypA protein; the single amino acid changes led to rapid degradation of the protein. CONCLUSIONS:We identified variants in PPIA that destabilize its product, CypA, and prevent HCV infection and replication. These findings indicate mechanisms by which some cells might be resistant to HCV infection and that CypA is a good therapeutic target.
journal_name
Gastroenterologyjournal_title
Gastroenterologyauthors
von Hahn T,Schiene-Fischer C,Van ND,Pfaender S,Karavul B,Steinmann E,Potthoff A,Strassburg C,Hamdi N,Abdelaziz AI,Sarrazin C,Müller T,Berg T,Trépo E,Wedemeyer H,Manns MP,Pietschmann T,Ciesek Sdoi
10.1053/j.gastro.2012.04.053subject
Has Abstractpub_date
2012-08-01 00:00:00pages
439-47.e1issue
2eissn
0016-5085issn
1528-0012pii
S0016-5085(12)00680-4journal_volume
143pub_type
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