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J. Virol. doi:10.1128/JVI.01585-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

IgA is a natural ligand of the Hepatitis A virus cellular receptor 1, and their association enhances virus-receptor interactions

Laboratory of Hepatitis and Related Emerging Agents, CBER, Food and Drug Administration, Bethesda, MD 20892, US; Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115, US; Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, US; and Division of Immunology, Karp Laboratories, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, US

^* To whom correspondence should be addressed. Email: GK{at}helix.nih.gov.

	Abstract

The Hepatitis A virus cellular receptor I (HAVCR1/TIM1), a member of the T cell immunoglobulin mucin (TIM) family, is an important atopy susceptibility gene in humans. The exact natural function of HAVCR1/TIM1 and the inverse association between HAV infection and prevention of atopy are not well understood. To identify natural ligands of human HAVCR1/TIM1, we used an expression cloning strategy based on the binding of dog cells transfected with a human lymph node cDNA library to an HAVCR1/TIM1 Fc fusion protein. The transfected cells that bound to the human HAVCR1/TIM1 Fc contained cDNA of human immunoglobulin alpha-1 heavy (Ig1) and lambda light (Ig) chain, and secreted human IgA1 antibody that bound to the cell surface. Cotransfection of the isolated Ig1 and Ig cDNAs to naïve dog cells resulted in the secretion of IgA1 that bound to HAVCR1/TIM1 Fc but not to a poliovirus receptor Fc fusion protein in a capture ELISA. The interaction of HAVCR1/TIM1with IgA was inhibited with monoclonal antibodies (mAb) against Ig1 and Ig, excess IgA1, or anti-HAVCR1/TIM1 mAb. IgA did not inhibit HAV infection of African green monkey cells suggesting that the IgA and the virus binding sites are in different epitopes on the HAVCR1/TIM1. IgA enhanced significantly the neutralization of HAV by HAVCR1/TIM1 Fc. Our results indicate that IgA1 is a specific ligand of HAVCR1/TIM1 and that their association has a synergistic effect in virus-receptor interactions.

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