Interaction of hepatitis C virus with lipoproteins and its role for infection and virus persistence

The cellular protein ABHD5 (stained in red) concentrates at the surface of the so-called lipid droplets (shown in green) in liver cells. Lipid droplets store lipids in the cells and play an important role in the assembly of Hepatitis C Virus particles. ABHD5 is one of the factors involved in this process. The nuclei of the cells are stained in blue.

Chronic infection with the hepatitis C virus (HCV) remains a global health problem. While curative therapies are available, many patients are unaware of their infection, and high treatment costs limit access to therapies, particularly in resource poor areas of the world where HCV prevalence is greatest. Moreover, treatment-induced viral clearance does not protect from reinfection. Thus, a prophylactic vaccine is needed to further reduce HCV-associated disease burden. HCV has evolved multiple strategies to evade innate, cellular and humoral immune responses thus allowing it to establish chronic infections. The association of HCV particles with human lipoproteins facilitates homing of virus particles to the liver and it mediates escape from neutralizing antibodies. Moreover, genetic variation in human lipoprotein genes like ApoE may influence the course of HCV infection.

In this project, Thomas Pietschmann and his staff are investigating the principles that govern the interaction between HCV and human lipoproteins and how association with lipoproteins facilitates cell entry and escape from antibodies. The ultimate goal is to use this information to guide development of HCV vaccination strategies. Up to now, cellular pathways and machineries involved in the interaction between HCV and lipoproteins are not fully understood. This projects aims at unravelling these connections by a variety of methods established in the laboratory of Thomas Pietschmann.

Scientific work programme

We characterize the structure and function of cellular and viral multi-protein complexes in the process of HCV assembly by using a combination of cell biological, viral, and quantitative proteome approaches. By using this approach and several viral mutants arrested at distinct steps of HCV assembly and release we explore the function and composition of multi-protein complexes in the course of assembly and viral maturation. Targets identified by these analyses are confirmed by RNA interference. Detailed analysis of HCV particle composition, specific infectivity, receptor interactions as well as neutralization by antibodies reveals the influence of lipoprotein interaction on the HCV entry process.
Collectively, this work will help us to define cellular factors that coordinate HCV lipoprotein interaction and in turn facilitate virus persistence.

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Thomas Pietschmann is talking about his research at CRC 900

Thomas Pietschmann has been part of the CRC since it was founded in 2010. His project A6 investigates the interactions of the hepatitis C virus with human lipoproteins.

Publications of the project A6

  • HCV Pit Stop at the Lipid Droplet: Refuel Lipids and Put on a Lipoprotein Coat before Exit. Vieyres G, Pietschmann T. T. Cells. 2019 Mar 12;8(3). pii: E233.

  • Hepatitis C virus strain-dependent usage of apolipoprotein E modulates assembly efficiency and specific inactivity of secreted virions. Weller R, Hueging K, Brown RJP, Todt D, Joecks S, Vondran FWR, Pietschmann T. J Virol. 2017 Jun 28. pii: JVI.00422-17.

  • Conformational flexibility in the immunoglobulin-like domain of the Hepatitis C Virus Glykoprotein E2. Vasiliauskaite I, Owsianka A, England P, Khan AG, Cole S, Bankwitz D, Foung SKH, Pietschmann T, Marcotrigiano J, Rey FA, Patel AH, Krey T. MBio. 2017 May 16;8(3). pii: e00382-17.

  • Maturation of secreted HCV particles by incorporation of secreted apoE protects from antibodies by enhancing infectivity. Bankwitz D, Doepke M, Hueging K, Weller R, Bruening J, Behrendt P, Lee JY, Vondran FWR, Manns MP, Bartenschlager R, Pietschmann T. J Hepatol. 2017 Apr 21. pii: S0168-8278(17)30251-9.

  • cGAS-Mediated Innate Immunity Spreads Intercellularly through HIV-1 Env-Induced Membrane Fusion Sites. Xu S, Ducroux A, Ponnurangam A, Vieyres G, Franz S, Müsken M, Zillinger T, Malassa A, Ewald E, Hornung V, Barchet W, Häussler S, Pietschmann T, Goffinet C. Cell Host Microbe. 2016 Oct 12;20(4):443-457.

  • ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production. Vieyres G, Welsch K, Gerold G, Gentzsch J, Kahl S, Vondran F, Kaderali L, Pietschmann T. PLOS Pathog. 2016 Apr 28;12(4):e1005568

  • Transcriptome analysis reveals a classical interferon signature induced by IFNλ4 in human primary cells. Lauber C, Vieyres G, Terczyńska-Dyla E, Anggakusuma, Dijkman R, Gad HH, Akhtar H, Geffers R, Vondran FW, Thiel V, Kaderali L, Pietschmann T, Hartmann R. Genes Immun. 2015 Sep;16(6):414-21.

  • Interferon-inducible cholesterol-25-hydroxylase restricts hepatitis C virus replication through blockage of membranous web formation. Anggakusuma, Romero-Brey I, Berger C, Colpitts CC, Boldanova T, Engelmann M, Todt D, Perin PM, Behrendt P, Vondran FW, Xu S, Goffinet C, Schang LM, Heim MH, Bartenschlager R, Pietschmann T, Steinmann E. Hepatology. 2015 Sep;62(3):702-14.

  • Decoding protein networks during virus entry by quantitative proteomics. Gerold G, Bruening J, Pietschmann T. Virus Res. 2015 Sep 10. pii: S0168-1702(15)30061-7.

  • Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice. Vercauteren K, Brown RJ, Mesalam AA, Doerrbecker J, Bhuju S, Geffers R, Van Den Eede N, McClure CP, Troise F, Verhoye L, Baumert T, Farhoudi A, Cortese R, Ball JK, Leroux-Roels G, Pietschmann T, Nicosia A, Meuleman P. Gut. 2015 Aug 25. pii: gutjnl-2014-309045.

  • Quantitative Proteomics Identifies Serum Response Factor Binding Protein 1 as a Host Factor for Hepatitis C Virus Entry. Gerold G, Meissner F, Bruening J, Welsch K, Perin PM, Baumert TF, Vondran FW, Kaderali L, Marcotrigiano J, Khan AG, Mann M, Rice CM, Pietschmann T. Cell Rep. 2015 Aug 4;12(5):864-78.

  • Several Human Liver Cell Expressed Apolipoproteins Complement HCV Virus Production with Varying Efficacy Conferring Differential Specific Infectivity to Released Viruses. Hueging K, Weller R, Doepke M, Vieyres G, Todt D, Wölk B, Vondran FW, Geffers R, Lauber C, Kaderali L, Penin F, Pietschmann T. PLoS One. 2015 Jul 30;10(7):e0134529.

  • Genetic Diversity Underlying the Envelope Glycoproteins of Hepatitis C Virus: Structural and Functional Consequences and the Implications for Vaccine Design. Tarr AW, Khera T, Hueging K, Sheldon J, Steinmann E, Pietschmann T, Brown RJ. Viruses. 2015 Jul 17;7(7):3995-4046. Review

  • Efficient virus assembly, but not infectivity, determines the magnitude of hepatitis C virus-induced interferon alpha responses of plasmacytoid dendritic cells. Grabski E, Wappler I, Pfaender S, Steinmann E, Haid S, Dzionek A, Pietschmann T, Kalinke U. J Virol. 2015 Mar;89(6):3200-8.

  • Role of hypervariable region 1 for the interplay of hepatitis C virus with entry factors and lipoproteins. Bankwitz D, Vieyres G, Hueging K, Bitzegeio J, Doepke M, Chhatwal P, Haid S, Catanese MT, Zeisel MB, Nicosia A, Baumert TF, Kaderali L, Pietschmann T. J Virol. 2014 Nov;88(21):12644-55.

  • Successful anti-scavenger receptor class B type I (SR-BI) monoclonal antibody therapy in humanized mice after challenge with HCV variants with in vitro resistance to SR-BI-targeting agents. Vercauteren K, Van Den Eede N, Mesalam AA, Belouzard S, Catanese MT, Bankwitz D, Wong-Staal F, Cortese R, Dubuisson J, Rice CM, Pietschmann T, Leroux-Roels G, Nicosia A, Meuleman P. Hepatology. 2014 Nov;60(5):1508-18.

  • In sero veritas: what serum markers teach us about HCV infection of primary human hepatocytes. Pietschmann T. Gut. 2014 Sep;63(9):1375-7. Commentary

  • Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells. Anggakusuma, Colpitts CC, Schang LM, Rachmawati H, Frentzen A, Pfaender S, Behrendt P, Brown RJ, Bankwitz D, Steinmann J, Ott M, Meuleman P, Rice CM, Ploss A, Pietschmann T, Steinmann E. Gut. 2014 Jul;63(7):1137-49.

  • Apolipoprotein E codetermines tissue tropism of hepatitis C virus and is crucial for viral cell-to-cell transmission by contributing to a postenvelopment step of assembly. Hueging K, Doepke M, Vieyres G, Bankwitz D, Frentzen A, Doerrbecker J, Gumz F, Haid S, Wölk B, Kaderali L, Pietschmann T. J Virol. 2014 Feb;88(3):1433-46.

  • Cell culture systems for hepatitis C virus. Steinmann E, Pietschmann T. Curr Top Microbiol Immunol. 2013;369:17-48.

  • Hepatitis C Virus p7 is Critical for Capsid Assembly and Envelopment. Gentzsch J, Brohm C, Steinmann E, Friesland M, Menzel N, Vieyres G, Perin PM, Frentzen A, Kaderali L, Pietschmann T. PLoS Pathog. 2013;9(5):e1003355.

  • Entry and replication of recombinant hepatitis C viruses in cell culture. Vieyres G, Pietschmann T. Methods. 2013 Feb;59(2):233-48.

  • MAP-kinase regulated cytosolic phospholipase A2 activity is essential for production of infectious hepatitis C virus particles. Menzel N, Fischl W, Hueging K, Bankwitz D, Frentzen A, Haid S, Gentzsch J, Kaderali L, Bartenschlager R, Pietschmann T. PLoS Pathog. 2012;8(7):e1002829.

  • Bile acids specifically increase hepatitis C virus RNA-replication. Chhatwal P, Bankwitz D, Gentzsch J, Frentzen A, Schult P, Lohmann V, Pietschmann T. PLoS One. 2012;7(4):e36029.

Contact

Prof. Thomas Pietschmann

TWINCORE – Centre for Clinical and Experimental Infection Research
Experimental Virology
Feodor-Lynen Str. 7
30265 Hannover

  +49 511 220027-130
 Thomas.Pietschmann@twincore.de

 Project at the homepage of TWINCORE