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Enhanced inhibition of hepatitis B virus production by asialoglycoprotein receptor-directed interferon

Nature Medicine volume 5, pages 577–581 (1999)Cite this article

Abstract

Most chronic carriers of hepatitis B virus (HBV) do not respond to interferon (IFN) treatment. This limitation of IFN therapy may be due in part to scant expression of IFN receptor in the liver1,2. Because the asialoglycoprotein (ASGP) receptor is specifically expressed in the liver at high density3, the ASGP receptor-binding domain was generated within an N-glycosylated human IFN-β molecule4,5 by the removal of sialic acid to direct this cytokine to the liver. This modified IFN (asialo-IFN-β) demonstrated greater inhibition of HBV production in ASGP receptor-positive human liver cells transfected with a replication-competent HBV construct than did conventional IFN-α or IFN-β. Furthermore, the enhanced antiviral effect of asialo-IFN-β was supported by induction of the 2'-5' oligoadenylate synthetase, an indicator of IFN activity6, at a level significantly higher than that produced by conventional IFN-β. Moreover, mouse asialo-IFN-β profoundly reduced viremia in vivo in HBV-transfected athymic nude mice, in contrast to conventional IFN-β, which had no substantial effect. These experiments demonstrate that directing IFN to ASGP receptor facilitates its signaling in the liver and augments its antiviral effect, and is therefore useful in overcoming the limited antiviral effect of conventional IFNs.

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Figure 1: Effect of asialo-IFN-β on the production of HBV virions.
Figure 2: Role of ASGP and IFN receptors in the enhanced antiviral effect of asialo-IFN-β.
Figure 3: In vivo antiviral effects of mouse and asialo-IFN-β.

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Acknowledgements

We thank S. Goelz (Biogen) and S. Yamazaki (Toray Industries) for the preparations of mouse and human IFN-βs; V. Trubetskoy and V. Torchilin for the preparation of in vivo transfection reagents; D. Frederick for technical assistance; T. Takehara, J.L. Dienstag and D.K. Podolsky for critical review of this manuscript; and H. Tsubouchi for support of T.E. This work was supported by Grants CA57584 and NIDDK4331 from the National Institutes of Health and an Educational Grant from Toray Industries.

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  1. Gastrointestinal Unit, Harvard Medical School and Massachusetts General Hospital, Jackson 7, Fruit St., Boston , 02114, Massachusetts, USA

    Toshiharu Eto & Hiroshi Takahashi

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  2. Hiroshi Takahashi
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Correspondence to Hiroshi Takahashi.

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Eto, T., Takahashi, H. Enhanced inhibition of hepatitis B virus production by asialoglycoprotein receptor-directed interferon. Nat Med 5, 577–581 (1999). https://doi.org/10.1038/8462

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