Elimination of hepatitis C virus from hepatocytes by a selective activation of therapeutic molecules.
To eliminate hepatitis C virus (HCV) from infected hepatocytes, we generated two therapeutic molecules specifically activated in cells infected with HCV. A dominant active mutant of interferon (IFN) regulatory factor 7 (IRF7) and a negative regulator of HCV replication, VAP-C (Vesicle-associated membrane protein-associated protein subtype C), were fused with the C-terminal region of IPS-1 (IFNβ promoter stimulator-1), which includes an HCV protease cleavage site that was modified to be localized on the ER membrane, and designated cIRF7 and cVAP-C, respectively. In cells expressing the HCV protease, cIRF7 was cleaved and the processed fragment was migrated into the nucleus, where it activated various IFN promoters, including promoters of IFNα6, IFNβ, and IFN stimulated response element. Activation of the IFN promoters and suppression of viral RNA replication were observed in the HCV replicon cells and in cells infected with the JFH1 strain of HCV (HCVcc) by expression of cIRF7. Suppression of viral RNA replication was observed even in the IFN-resistant replicon cells by the expression of cIRF7. Expression of the cVAP-C also resulted in suppression of HCV replication in both the replicon and HCVcc infected cells. These results suggest that delivery of the therapeutic molecules into the liver of hepatitis C patients, followed by selective activation of the molecules in HCV-infected hepatocytes, is a feasible method for eliminating HCV.
Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Xiaoyu
X
Wen
Takayuki
T
Abe
Hiroshi
H
Kukihara
Shuhei
S
Taguwa
Yoshio
Y
Mori
Hideki
H
Tani
Nobuyuki
N
Kato
Tetsuro
T
Suzuki
Masashi
M
Tatsumi
Kohji
K
Moriishi
Yoshiharu
Y
Matsuura
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000138:chemical synthesis; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000627:therapeutic use; D015202:Protein Engineering / Q000379:methods*; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000235:genetics / Q000627:therapeutic use; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D050839:Interferon Regulatory Factor-7; C505371:MAVS protein, human; D011993:Recombinant Fusion Proteins; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins
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