title: Molecular chaperone Hsp90 is a therapeutic target for noroviruses.
abstract: Human noroviruses (HuNoV) are a significant cause of acute gastroenteritis in the developed world, and yet our understanding of the molecular pathways involved in norovirus replication and pathogenesis has been limited by the inability to efficiently culture these viruses in the laboratory. Using the murine norovirus (MNV) model, we have recently identified a network of host factors that interact with the 5' and 3' extremities of the norovirus RNA genome. In addition to a number of well-known cellular RNA binding proteins, the molecular chaperone Hsp90 was identified as a component of the ribonucleoprotein complex. Here, we show that the inhibition of Hsp90 activity negatively impacts norovirus replication in cell culture. Small-molecule-mediated inhibition of Hsp90 activity using 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) revealed that Hsp90 plays a pleiotropic role in the norovirus life cycle but that the stability of the viral capsid protein is integrally linked to Hsp90 activity. Furthermore, we demonstrate that both the MNV-1 and the HuNoV capsid proteins require Hsp90 activity for their stability and that targeting Hsp90 in vivo can significantly reduce virus replication. In summary, we demonstrate that targeting cellular proteostasis can inhibit norovirus replication, identifying a potential novel therapeutic target for the treatment of norovirus infections.
  
  
  OBJECTIVE
  HuNoV are a major cause of acute gastroenteritis around the world. RNA viruses, including noroviruses, rely heavily on host cell proteins and pathways for all aspects of their life cycle. Here, we identify one such protein, the molecular chaperone Hsp90, as an important factor required during the norovirus life cycle. We demonstrate that both murine and human noroviruses require the activity of Hsp90 for the stability of their capsid proteins. Furthermore, we demonstrate that targeting Hsp90 activity in vivo using small molecule inhibitors also reduces infectious virus production. Given the considerable interest in the development of Hsp90 inhibitors for use in cancer therapeutics, we identify here a new target that could be explored for the development of antiviral strategies to control norovirus outbreaks and treat chronic norovirus infection in immunosuppressed patients.
authors: Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom sv345@cam.ac.uk ig299@cam.ac.uk.
authors: Surender
authors: http://orcid.org/0000-0003-1343-8514
authors: S
authors: Vashist
authors: Section of Virology, Imperial College London, St. Mary's Campus, London, United Kingdom.
authors: Luis
authors: L
authors: Urena
authors: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Mariam B
authors: MB
authors: Gonzalez-Hernandez
authors: Department of Pathology, University of Chicago, Chicago, Illinois, USA.
authors: Jayoung
authors: J
authors: Choi
authors: National Reference Centre for Enteric Viruses, Public Hospital of Dijon, University of Bourgogne, Dijon, France.
authors: Alexis
authors: http://orcid.org/0000-0002-3084-9414
authors: A
authors: de Rougemont
authors: KU Leuven-University of Leuven, Rega Institute for Medical Research, Leuven, Belgium.
authors: Joana
authors: J
authors: Rocha-Pereira
authors: KU Leuven-University of Leuven, Rega Institute for Medical Research, Leuven, Belgium.
authors: Johan
authors: J
authors: Neyts
authors: Department of Pathology, University of Chicago, Chicago, Illinois, USA.
authors: Seungmin
authors: S
authors: Hwang
authors: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Christiane E
authors: CE
authors: Wobus
authors: Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom sv345@cam.ac.uk ig299@cam.ac.uk.
authors: Ian
authors: I
authors: Goodfellow
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use; D017250:Caliciviridae Infections / Q000517:prevention & control; D002460:Cell Line; D002470:Cell Survival; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D007082:Ileum / Q000821:virology; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use; D008807:Mice, Inbred BALB C; D029322:Norovirus / Q000502:physiology*; D019562:Viral Load; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin