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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Hepatocytes that express variants of cyclophilin a are resistant to HCV infection and replication
Gastroenterology, Volume 143, No. 2, Year 2012
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Description
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. © 2012 AGA Institute.
Authors & Co-Authors
von Hahn, Thomas
Germany, Hannover
Hannover Medical School
Schiene-Fischer, Cordelia
Germany, Halle
Max Planck Research Unit for Enzymology of Protein Folding
Van, Nguyendinh
Germany, Hannover
Hannover Medical School
Pfaender, Stephanie
Germany, Hannover
Twincore, Germany
Karavul, Behya
Germany, Hannover
Hannover Medical School
Steinmann, Eike
Germany, Hannover
Twincore, Germany
Potthoff, Andrej
Germany, Hannover
Hannover Medical School
Strassburg, Christian P.
Germany, Hannover
Hannover Medical School
Hamdi, Nabila
Egypt, New Cairo
Faculty of Pharmacy and Biotechnology
Abdelaziz, Ahmed Ihab
Egypt, New Cairo
Faculty of Pharmacy and Biotechnology
Sarrazin, Christoph M.
Germany, Frankfurt am Main
Universitätsklinikum Frankfurt
Mueller, Tobias
Germany, Berlin
Charité – Universitätsmedizin Berlin
Berg, Thomas
Germany, Leipzig
Universitätsklinikum Leipzig Und Medizinische Fakultät
Trépo, Eric
Belgium, Brussels
Hôpital Erasme
Wedemeyer, Heiner
Germany, Hannover
Hannover Medical School
Manns, Michael Peter
Germany, Hannover
Hannover Medical School
Pietschmann, Thomas
Germany, Hannover
Twincore, Germany
Ciesek, Sandra
Germany, Hannover
Hannover Medical School
Germany, Hannover
Twincore, Germany
Statistics
Citations: 31
Authors: 18
Affiliations: 8
Identifiers
Doi:
10.1053/j.gastro.2012.04.053
ISSN:
00165085
e-ISSN:
15280012
Research Areas
Genetics And Genomics
Infectious Diseases