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Journal of Virology, August 2003, p. 8765-8774, Vol. 77, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.16.8765-8774.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Alteration of Hepatitis A Virus (HAV) Particles by a Soluble Form of HAV Cellular Receptor 1 Containing the Immunoglobulin- and Mucin-Like Regions

Erica Silberstein,1 Li Xing,2 Willem van de Beek,2 Jinhua Lu,1 Holland Cheng,2 and Gerardo G. Kaplan1*

Laboratory of Hepatitis and Related Emerging Agents, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892,1 Department of Biosciences, Karolinska Institute, Stockholm 14157, Sweden2

Received 23 December 2002/ Accepted 23 May 2003

Hepatitis A virus (HAV) infects African green monkey kidney cells via HAV cellular receptor 1 (havcr-1). The ectodomain of havcr-1 contains an N-terminal cysteine-rich immunoglobulin-like region (D1), followed by a mucin-like region that extends D1 well above the cell surface. D1 is required for binding of HAV, and a soluble construct containing D1 fused to the hinge and Fc portions of human immunoglobulin G1 (IgG1), D1-Fc, bound and neutralized HAV inefficiently. However, D1-Fc did not alter the virions. To determine whether additional regions of havcr-1 are required to trigger uncoating of HAV, we constructed D1muc-Fc containing D1 and two-thirds of the mucin-like region fused to the Fc and hinge portions of human IgG1. D1muc-Fc neutralized 10 times more HAV than did D1-Fc. Sedimentation analysis in sucrose gradients showed that treatment of HAV with 20 to 200 nM D1muc-Fc disrupted the majority of the virions, whereas treatment with 2 nM D1muc-Fc had no effect on the sedimentation of the particles. Treatment of HAV with 100 nM D1muc-Fc resulted in low-level accumulation of 100- to 125S particles. Negative-stain electron microscopy analysis revealed that the 100- to 125S particles had the characteristics of disrupted virions, such as internal staining and diffuse edges. Quantitative PCR analysis showed that the 100- to 125S particles contained viral RNA. These results indicate that D1 and the mucin-like region of havcr-1 are required to induce conformational changes leading to HAV uncoating.

* Corresponding author. Mailing address: Laboratory of Hepatitis and Related Emerging Agents, DETTD, CBER, FDA, 8800 Rockville Pike, Bldg. 29, HFM-325, Bethesda, MD 20892. Phone: (301) 496-0338. Fax: (301) 480-7928. E-mail: GK{at}helix.nih.gov.

Journal of Virology, August 2003, p. 8765-8774, Vol. 77, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.16.8765-8774.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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