Down-regulation of viral replication by adenoviral-mediated expression of siRNA against cellular cofactors for hepatitis C virus.
Small interfering RNA (siRNA) is currently being evaluated not only as a powerful tool for functional genomics, but also as a potentially promising therapeutic agent for cancer and infectious diseases. Inhibitory effect of siRNA on viral replication has been demonstrated in multiple pathogenic viruses. However, because of the high sequence specificity of siRNA-mediated RNA degradation, antiviral efficacy of siRNA directed to viral genome will be largely limited by emergence of escape variants resistant to siRNA due to high mutation rates of virus, especially RNA viruses such as poliovirus and hepatitis C virus (HCV). To investigate the therapeutic feasibility of siRNAs specific for the putative cellular cofactors for HCV, we constructed adenovirus vectors expressing siRNAs against La, polypyrimidine tract-binding protein (PTB), subunit gamma of human eukaryotic initiation factors 2B (eIF2Bgamma), and human VAMP-associated protein of 33 kDa (hVAP-33). Adenoviral-mediated expression of siRNAs markedly diminished expression of the endogenous genes, and silencing of La, PTB, and hVAP-33 by siRNAs substantially blocked HCV replication in Huh-7 cells. Thus, our studies demonstrate the feasibility and potential of adenoviral-delivered siRNAs specific for cellular cofactors in combating HCV infection, which can be used either alone or in combination with siRNA against viral genome to prevent the escape of mutant variants and provide additive or synergistic anti-HCV effects.
Zhang
Jing
J
Research and Development Center, FUSO Pharmaceutical Industries, LTD, Joto-ku, Osaka 536-8523, Japan. j-zhang@fuso-pharm.co.jp
Yamada
Osamu
O
Sakamoto
Takashi
T
Yoshida
Hiroshi
H
Iwai
Takahiro
T
Matsushita
Yoshihisa
Y
Shimamura
Hideo
H
Araki
Hiromasa
H
Shimotohno
Kunitada
K
D000251:Adenosine Triphosphatases / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D001324:Autoantigens; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D015536:Down-Regulation; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics; D034741:RNA, Small Interfering / Q000096:biosynthesis*; D012261:Ribonucleoproteins / Q000235:genetics; D014162:Transfection; D033921:Vesicular Transport Proteins; D014779:Virus Replication / Q000502:physiology; D000097585:SS-B Antigen
D000251:Adenosine Triphosphatases; D001324:Autoantigens; D002352:Carrier Proteins; D020717:Eukaryotic Initiation Factor-2B; D008565:Membrane Proteins; D038941:Polypyrimidine Tract-Binding Protein; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins; D033921:Vesicular Transport Proteins; D000097585:SS-B Antigen; C114051:VAPA protein, human