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bioRxiv · 10.1101/2022.12.05.519105

Hepatitis E virus genome replication is independent of cyclophilins A and B

Buchanan, F. J.·Chen, S.·Harris, M.·Herod, M. R.
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Abstract

Hepatitis E virus (HEV) is an emerging pathogen responsible for more than 20 million cases of acute hepatitis globally per annum. Healthy individuals typically have a self-limiting infection, however, mortality rates in some populations such as pregnant women can reach 30%. A detailed understanding of the virus lifecycle is lacking, mainly due to limitations in experimental systems. In this regard, the cyclophilins are an important family of proteins that have peptidyl-prolyl isomerase activity and play roles in the replication of a number of positive-sense RNA viruses, including hepatotropic viruses such as hepatitis C virus (HCV). Cyclophilin A (CypA) and cyclophilin B (CypB) are the two most abundant human cyclophilins in hepatocytes and are therefore potential targets for pan-viral therapeutics. Here, we investigated the importance of CypA and CypB for HEV genome replication using a sub-genomic replicon system. This system removes the requirements for viral entry and packaging and therefore allows for the sensitive measurement of viral genome replication in isolation. Using pharmacological inhibition by cyclosporine A (CsA), known to suppress HCV replication, and silencing by shRNA we find that CypA and CypB are not essential for replication of genotype 1 or 3 HEV replication. However, we find that silencing of CypB reduces replication of genotype 1 HEV in some cells, but not genotype 3. These data suggests HEV is atypical in its requirements for cyclophilin for viral genome replication and that this phenomenon could be genotype specific.

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Buchanan, F. J., Chen, S., Harris, M., Herod, M. R.. 2022-12-05. Hepatitis E virus genome replication is independent of cyclophilins A and B. https://doi.org/10.1101/2022.12.05.519105

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