Antiviral activity and RNA polymerase degradation following Hsp90 inhibition in a range of negative strand viruses.
We have analyzed the effectiveness of Hsp90 inhibitors in blocking the replication of negative-strand RNA viruses. In cells infected with the prototype negative strand virus vesicular stomatitis virus (VSV), inhibiting Hsp90 activity reduced viral replication in cells infected at both high and low multiplicities of infection. This inhibition was observed using two Hsp90 inhibitors geldanamycin and radicicol. Silencing of Hsp90 expression using siRNA also reduced viral replication. Hsp90 inhibition changed the half-life of newly synthesized L protein (the large subunit of the VSV polymerase) from >1 h to less than 20 min without affecting the stability of other VSV proteins. Both the inhibition of viral replication and the destabilization of the viral L protein were seen when either geldanamycin or radicicol was added to cells infected with paramyxoviruses SV5, HPIV-2, HPIV-3, or SV41, or to cells infected with the La Crosse bunyavirus. Based on these results, we propose that Hsp90 is a host factor that is important for the replication of many negative strand viruses.
Connor
John H
JH
Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA. jhconnor@bu.edu
McKenzie
Margie O
MO
Parks
Griffith D
GD
Lyles
Douglas S
DS
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D018109:Avulavirus / Q000187:drug effects / Q000254:growth & development; D016227:Benzoquinones / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D018062:La Crosse virus / Q000187:drug effects / Q000254:growth & development; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D012328:RNA Viruses / Q000187:drug effects* / Q000254:growth & development; D034741:RNA, Small Interfering; D012324:RNA-Dependent RNA Polymerase / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects / Q000254:growth & development; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; D034741:RNA, Small Interfering; D014764:Viral Proteins; C040530:L protein, vesicular stomatitis virus; D012324:RNA-Dependent RNA Polymerase; D012321:DNA-Directed RNA Polymerases; D046988:Proteasome Endopeptidase Complex; C035359:monorden; C001277:geldanamycin