Chikungunya virus nsP3 & nsP4 interacts with HSP-90 to promote virus replication: HSP-90 inhibitors reduce CHIKV infection and inflammation in vivo
Autor(es): Rathore Abhay P S,Haystead Timothy,Das Pratyush K,Merits -res,Ng Mah-Lee,Vasudevan Subhash G
Resumo: The global emergence of Chikungunya virus (CHIKV) infection is alarming - currently there is no licensed vaccine or antiviral treatment available to mitigate this disease. CHIKV infection typically results in high viral load with an outcome of high fever, skin rashes, muscle pain, - sequelae of prolonged arthritis, which occurs in >90% of the infected cases. In this study, using biochemical pull-downs, mass-spectrometry, - microscopic imaging techniques, we have identified novel interactions between CHIKV nsP3 or nsP4 proteins with the host stress-pathway chaperone HSP-90 protein. Indeed, silencing of HSP-90 transcripts using siRNA disrupts CHIKV replication in cultured cells. Furthermore, drugs targeting HSP-90, such as commercially available geldanamycin, as well as other specific HSP-90 inhibitor drugs that had been obtained from a purinome mining approach (HS-10 - SNX-2112) showed dramatic reduction in viral titers - reduced inflammation in a CHIKV mouse model of severe infection - musculopathy. The detailed study of the underlying molecular mechanism of these viral - host protein interactions may provide a platform to develop novel therapeutics against CHIKV infection.
Palavras-Chave: CHIKV mouse model; CHIKV nsP3; CHIKV nsP4; Geldanamycin; HSP-90; Protein interactions
Imprenta: Antiviral Research, v. 103, p. 7-16, 2014
Identificador do objeto digital: 10.1016/j.antiviral.2013.12.010
Descritores: Chikungunya virus - Biosynthesis ; Chikungunya virus - Cell ; Chikungunya virus - Cytopathology ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Proteins ; Chikungunya virus - Infectious diseases ; Chikungunya virus - Inflammation ; Chikungunya virus - Viral infections ; Chikungunya Virus - Virus ; Chikungunya virus - Vaccine ; Chikungunya virus - Chikungunya fever
Data de publicação: 2014
