Elimination of hepatitis C virus from hepatocytes by a selective activation of therapeutic molecules

Xiaoyu Wen, Takayuki Abe, Hiroshi Kukihara, Shuhei Taguwa, Yoshio Mori, Hideki Tani, Nobuyuki Kato, Tetsuro Suzuki, Masashi Tatsumi, Kohji Moriishi, Yoshiharu Matsuura

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere15967
JournalPLoS One
Volume6
Issue number1
DOIs
Publication statusPublished - 2011

Fingerprint

Hepatitis C virus
Viruses
Hepacivirus
hepatocytes
Hepatocytes
Chemical activation
interferons
therapeutics
Molecules
Interferons
replicon
Replicon
promoter regions
Therapeutics
Viral RNA
cells
Virus Replication
virus replication
Interferon Regulatory Factor-7
Peptide Hydrolases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Wen, X., Abe, T., Kukihara, H., Taguwa, S., Mori, Y., Tani, H., ... Matsuura, Y. (2011). Elimination of hepatitis C virus from hepatocytes by a selective activation of therapeutic molecules. PLoS One, 6(1), [e15967]. https://doi.org/10.1371/journal.pone.0015967

Elimination of hepatitis C virus from hepatocytes by a selective activation of therapeutic molecules. / Wen, Xiaoyu; Abe, Takayuki; Kukihara, Hiroshi; Taguwa, Shuhei; Mori, Yoshio; Tani, Hideki; Kato, Nobuyuki; Suzuki, Tetsuro; Tatsumi, Masashi; Moriishi, Kohji; Matsuura, Yoshiharu.

In: PLoS One, Vol. 6, No. 1, e15967, 2011.

Research output: Contribution to journalArticle

Wen, X, Abe, T, Kukihara, H, Taguwa, S, Mori, Y, Tani, H, Kato, N, Suzuki, T, Tatsumi, M, Moriishi, K & Matsuura, Y 2011, 'Elimination of hepatitis C virus from hepatocytes by a selective activation of therapeutic molecules', PLoS One, vol. 6, no. 1, e15967. https://doi.org/10.1371/journal.pone.0015967
Wen, Xiaoyu ; Abe, Takayuki ; Kukihara, Hiroshi ; Taguwa, Shuhei ; Mori, Yoshio ; Tani, Hideki ; Kato, Nobuyuki ; Suzuki, Tetsuro ; Tatsumi, Masashi ; Moriishi, Kohji ; Matsuura, Yoshiharu. / Elimination of hepatitis C virus from hepatocytes by a selective activation of therapeutic molecules. In: PLoS One. 2011 ; Vol. 6, No. 1.
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