@article{685943b6aa124390a185b363b16bd4cb,
title = "Differences across cyclophilin a orthologs contribute to the host range restriction of hepatitis c virus",
abstract = "The restricted host tropism of hepatitis C virus (HCV) remains incompletely understood, especially post-entry, and has hindered developing an immunocompetent, small animal model. HCV replication in non-permissive species may be limited by incompatibilities between the viral replication machinery and orthologs of essential host factors, like cyclophilin A (CypA). We thus compared the ability of CypA from mouse, tree shrew, and seven non-human primate species to support HCV replication, finding that murine CypA only partially rescued viral replication in Huh7.5-shRNA CypA cells. We determined the specific amino acid differences responsible and generated mutants able to fully rescue replication. We expressed these mutants in engineered murine hepatoma cells and although we observed increases in HCV replication following infection, they remained far lower than those in highly permissive human hepatoma cells, and minimal infectious particle release was observed. Together, these data suggest additional co-factors remain unidentified. Future work to determine such factors will be critical for developing an immunocompetent mouse model supporting HCV replication.",
author = "Gaska, {Jenna M.} and Metodi Balev and Qiang Ding and Brigitte Heller and Alexander Ploss",
note = "Funding Information: NIHNational Institutes of Health Training grant 4T32GM007388-40 Jenna M Gaska State of New Jersey Depart- ment of Health and Senior Services New Jersey Commission on Cancer Research DHFS16PPC007 Qiang Ding NIHNational Institutes of HealthR01AI107301 Alexander Ploss American Cancer Society RSG-15-048-01-MPC Alexander Ploss Burroughs Wellcome Fund 101539 Alexander Ploss Cancer Institute of New Jersey Cancer Center Support Grant P30CA072720 Alexander Ploss The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Funding Information: We would like to thank Charles Rice (Rockefeller University) for Huh7.5 cells; the J6/JFH and Jc1 genomes; and the monoclonal 9E10 antibody. We would also like to thank Frank Chisari (The Scripps Research Institute) for the Huh7.5.1 cells. We thank Thomas von Hahn (Hannover Medical School, Germany) and Sandra Ciesek (University of Duisburg-Essen, Germany) for providing the Huh7.5-shRNA CypA and Huh7.5-shRNA irrel cells. We are grateful to Christina DeCoste and Katherine Rit-tenbach of the Flow Cytometry Resource Facility at Princeton University for their assistance in the planning and execution of all flow cytometry experiments. The Flow Cytometry core facility is partially supported by the Cancer Institute of New Jersey Cancer Center Support Grant (P30CA072720). This research is funded by the NIH (R01AI107301-06 to AP); the American Cancer Society (RSG-15-048-01-MPC to AP); and a Burroughs Wellcome Fund Award for Investigators in Pathogenesis (to AP). QD was supported by a postdoctoral fellowship from the New Jersey Commission on Cancer Research (DHFS16PPC007) and JMG by an NIH training grant (4T32GM007388-40). Publisher Copyright: {\textcopyright} Gaska et al.",
year = "2019",
month = may,
doi = "10.7554/eLife.44436",
language = "English (US)",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}