Control of Hepatitis C Virus replication by viral and cellular factors

Research area: Molecular Virology

Replication of Hepatitis C Virus (HCV) genome RNA in cells requires both the establishment and specific activity of viral RNA replication complexes and also viral countermeasures against the cellular innate immune system. We found that HCV stimulates expression of a long non-coding RNA (Lnc-ITM2C-1 or GCSIR) that in turn stimulates expression of a cannabinoid receptor, GPR55. This in turn suppresses expression of interferon-stimulated genes (ISGs) in favour of HCV replication. In this project, we aim at gaining deeper insight into the molecular mechanisms of the Lnc-ITM2C-1 – GPR55 – ISG regulation axis. Complementary to the early steps of the cellular response, we aim at elucidating the early steps of HCV RNA synthesis in cells, using full-length and subgenomic replicon systems. Ribosome pausing at two positions at the NS5B replicase stop codon and directly upstream is caused by inefficient codons, indicating that a slow-down of NS5B translation may be important for the initiation of minus strand synthesis. We want to identify HCV RNA cis-signals and long-range interactions involved in the balance of initial RNA genome translation starting at the genome´s 5´-end versus the initiation of RNA minus strand synthesis starting at the genome´s 3´-end.

Project-related publications of the investigator:

  • Niepmann M, Gerresheim GK. 2020. Hepatitis C Virus Translation Regulation. Int J Mol Sci 21.
  • Gerresheim GK, Hess CS, Shalamova LA, Fricke M, Marz M, Andreev DE, Shatsky IN, Niepmann M. 2020. Ribosome Pausing at Inefficient Codons at the End of the Replicase Coding Region Is Important for Hepatitis C Virus Genome Replication. Int J Mol Sci 21.
  • Hu P, Wilhelm J, Gerresheim GK, Shalamova LA, Niepmann M. 2019. Lnc-ITM2C-1 and GPR55 Are Proviral Host Factors for Hepatitis C Virus. Viruses 11.
  • Gerresheim GK, Roeb E, Michel AM, Niepmann M. 2019. Hepatitis C Virus Downregulates Core Subunits of Oxidative Phosphorylation, Reminiscent of the Warburg Effect in Cancer Cells. Cells 8.
  • Gerresheim GK, Bathke J, Michel AM, Andreev DE, Shalamova LA, Rossbach O, Hu P, Glebe D, Fricke M, Marz M, Goesmann A, Kiniry SJ, Baranov PV, Shatsky IN, Niepmann M. 2019. Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling. Int J Mol Sci 20.
  • Fricke M, Gerst R, Ibrahim B, Niepmann M, Marz M. 2019. Global importance of RNA secondary structures in protein-coding sequences. Bioinformatics 35:579-583.
  • Niepmann M, Shalamova LA, Gerresheim GK, Rossbach O. 2018. Signals Involved in Regulation of Hepatitis C Virus RNA Genome Translation and Replication. Front Microbiol 9:395.
  • Jost I, Shalamova LA, Gerresheim GK, Niepmann M, Bindereif A, Rossbach O. 2018. Functional sequestration of microRNA-122 from Hepatitis C Virus by circular RNA sponges. RNA Biol 15:1032-1039.
  • Nieder-Rohrmann A, Dunnes N, Gerresheim GK, Shalamova LA, Herchenrother A, Niepmann M. 2017. Cooperative enhancement of translation by two adjacent microRNA-122/Argonaute 2 complexes binding to the 5′ untranslated region of hepatitis C virus RNA. J Gen Virol 98:212-224.
  • Gerresheim GK, Dunnes N, Nieder-Rohrmann A, Shalamova LA, Fricke M, Hofacker I, Honer Zu Siederdissen C, Marz M, Niepmann M. 2017. microRNA-122 target sites in the hepatitis C virus RNA NS5B coding region and 3′ untranslated region: function in replication and influence of RNA secondary structure. Cell Mol Life Sci 74:747-760.