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Specific interaction of the envelope glycoproteins E1 and E2 with liver heparan sulfate involved in the tissue tropismatic infection by hepatitis C virus

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Abstract

The first step in the process of infections by the hepatitis C virus (HCV) is attachment to the host cell, which is assumed to be mediated by interaction of the envelope glycoproteins E1 and E2 with cell surface glycosaminoglycans. In this study, a variety of glycosaminoglycans, heparan sulfate (HS) from various bovine tissues as well as chondroitin sulfate (CS)/dermatan sulfate from bovine liver, were used to examine the direct interaction with recombinant E1 and E2 proteins. Intriguingly, among HS preparations from various bovine tissues, only liver HS strongly bound to both E1 and E2. Since HS from liver, which is the target tissue of HCV, contains highly sulfated structures compared to HS from other tissues, the present results suggest that HS-proteoglycan on the liver cell surface appears to be one of the molecules that define the liver-specific tissue tropism of HCV infection. The interaction assay with chemically modified heparin derivatives provided evidence that the binding of the viral proteins to heparin/HS is not only mediated by simple ionic interactions, but that the 6-O-sulfation and N-sulfation are important. Heparin oligosaccharides equal to or larger than 10-mer were required to inhibit the binding. Notably, a highly sulfated CS-E preparation from squid cartilage also strongly interacted with both viral proteins and inhibited the entry of pseudotype HCV into the target cells, suggesting that the highly sulfated CS-E might be useful as an anti-HCV drug.

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Abbreviations

2AB:

2-aminobenzamide

CDNA:

completely desulfated and N-acetylated heparin

CDNS:

completely desulfated and N-sulfated heparin

NDNA:

N-desulfated and N-acetylated heparin

2ODS:

2-O-desulfated heparin

6ODS:

6-O-desulfated heparin

CS:

chondroitin sulfate

DS:

dermatan sulfate

ELISA:

enzyme-linked immunosorbent assay

FGF:

fibroblast growth factor

GAG:

glycosaminoglycan

HCV:

hepatitis C virus

ΔHexA:

4-deoxy-α-L-threo-hex-4-enepyranosyluronic acid

HPLC:

high performance liquid chromatography

HS:

heparan sulfate

PG:

proteoglycan

VSV:

vesicular stomatitis virus

NS:

2-N-sulfate

2S:

2-O-sulfate

4S:

4-O-sulfate

6S:

6-O-sulfate

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Acknowledgments

The authors thank Satoko Ueno, Naoko Shoji, and Machiko Tomimatsu for technical assistance. This work was supported in part by Grants-in-aid for Scientific Research C-21590057 (to S. Y.), Scientific Research (B) 23390016 (to K. S.), and the Matching Program for Innovations in Future Drug Discovery and Medical Care (to K. S.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT).

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Author notes

  1. Shuhei Yamada

    Present address: Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Yagotoyama 150, Tempaku-ku, Nagoya, 468-8503, Japan

Authors and Affiliations

  1. Laboratory of Proteoglycan Signaling and Therapeutics, Hokkaido University Graduate School of Life Science, West-11, North-21, Kita-ku, Sapporo, 001-0021, Japan

    Fumi Kobayashi, Shuhei Yamada, Yoshiki Hama & Kazuyuki Sugahara

  2. Department of Biochemistry, Kobe Pharmaceutical University, Higashinada-ku, Kobe, 658-8558, Japan

    Shuhei Yamada, Satomi Naito & Kazuyuki Sugahara

  3. Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Yamada-oka 3-1, Suita-shi, Osaka, 565-0871, Japan

    Shuhei Taguwa, Chikako Kataoka, Hideki Tani & Yoshiharu Matsuura

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  1. Fumi Kobayashi
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Kobayashi, F., Yamada, S., Taguwa, S. et al. Specific interaction of the envelope glycoproteins E1 and E2 with liver heparan sulfate involved in the tissue tropismatic infection by hepatitis C virus. Glycoconj J 29, 211–220 (2012). https://doi.org/10.1007/s10719-012-9388-z

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