Differences across cyclophilin A orthologs contribute to the host range restriction of hepatitis C virus.

TitleDifferences across cyclophilin A orthologs contribute to the host range restriction of hepatitis C virus.
Publication TypeJournal Article
Year of Publication2019
AuthorsGaska, JM, Balev, M, Ding, Q, Heller, B, Ploss, A
JournalElife
Volume8
Date Published2019 May 10
ISSN2050-084X
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.

DOI10.7554/eLife.44436
Alternate JournalElife
PubMed ID31074414
PubMed Central IDPMC6510530
Grant List101539 / / Burroughs Wellcome Fund /
New Jersey Commission on Cancer Research DHFS16PPC007 / / State of New Jersey Department of Health and Senior Services /
P30 CA072720 / CA / NCI NIH HHS / United States
Support Grant P30CA072720 / / Cancer Institute of New Jersey Cancer Center /
Training grant 4T32GM007388-40 / / National Institutes of Health /
R01AI107301 / / National Institutes of Health /
T32 GM007388 / GM / NIGMS NIH HHS / United States
RSG-15-048-01-MPC / / American Cancer Society /
R01 AI107301 / AI / NIAID NIH HHS / United States