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Inhibition of Hepatitis C Virus using siRNAs targeted to the viral genome and cellular proteins HSPs

Grant number: 11/15786-4
Support type:Scholarships in Brazil - Master
Effective date (Start): March 01, 2012
Effective date (End): July 31, 2013
Field of knowledge:Biological Sciences - Microbiology
Principal Investigator:Paula Rahal
Grantee:Ana Cláudia Silva Braga
Home Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto, SP, Brazil

Abstract

Hepatitis C is a consequence of infection with hepatitis C virus (HCV) and it is estimated that approximately 170 million people are chronically infected. Recently it has been demonstrated several interactions between viral and host proteins during the HCV replication cycle and these interactions might create opportunities for a new strategy for therapies against hepatitis C. Despite the inhibition of viral proteins through RNAi pathway being relatively effective in reducing HCV replication, combined inhibition between viral and host proteins can reduce replication more efficiently on long-term treatments, because the rate of mutation of the host genome is lower than the virus and thus reducing the rates of viral evasion and providing a more sustained virologic response. Proteins belonging to the HSP family (heat shock proteins), are strong candidates for this new approach because proteins are not essential to the cell therefore it can be inhibited almost without causing damage. In addition, it has been demonstrated the interaction between HSP27, Hsp70 and Hsp90 proteins to HCV nonstructural proteins, such as NS3 and NS5A. The objective of this work is to inhibit viral replication using four siRNA molecules targeting viral genome in combination with siRNAs targeted to cellular proteins HSP27, Hsp70 and Hsp90. The siRNA molecules are transfected into Huh7 cells harboring a HCV sub-genomic replicon system (pSGR-JFH1) and evaluated for its effectiveness in inhibiting virus replication. The efficiency of siRNA molecules will be evaluated by real-time PCR and western blot and it is expected that the combined inhibition of cellular and viral proteins to be more efficient in reducing viral replication in a long-term evaluation.