Antiviral activity and RNA polymerase degradation following Hsp90 inhibition in a range of negative strand viruses

• Published in: Virology (New York, N.Y.) N.Y.), 2007-05, Vol.362 (1), p.109-119
• Main Authors: Connor, John H, McKenzie, Margie O, Parks, Griffith D, Lyles, Douglas S
• Format: Article
• Language: English
• Subjects: Animals; Antiviral; Antiviral Agents - pharmacology; Avulavirus - drug effects; Avulavirus - growth & development; Benzoquinones - pharmacology; Bunyavirus; Cell Line; Chaperone; Cricetinae; DNA-Directed RNA Polymerases - metabolism; HeLa Cells; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Hsp90 inhibitor; Humans; Infectious Disease; La Crosse virus; La Crosse virus - drug effects; La Crosse virus - growth & development; Lactams, Macrocyclic - pharmacology; Macrolides - pharmacology; Paramyxovirus; Polymerase; Proteasome Endopeptidase Complex - metabolism; RNA Interference; RNA Replicase - metabolism; RNA Viruses - drug effects; RNA Viruses - growth & development; RNA, Small Interfering; SV5; Vesicular stomatitis Indiana virus - drug effects; Vesicular stomatitis Indiana virus - growth & development; Vesicular stomatitis virus; Viral Proteins - metabolism; Virus Replication - drug effects
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2006.12.026

Abstract 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.