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J. Virol. doi:10.1128/JVI.00316-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Antibodies to envelope glycoprotein of dengue virus during the natural course of infection are predominantly cross-reactive and recognize epitopes containing highly conserved residues at the fusion loop of domain II

Institute of Microbiology, Department of Internal Medicine, Institute of Medical Technology, College of Medicine, and Institute of Epidemiology, College of Public Health, National Taiwan University, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan; Division of Vector-Borne Infectious Diseases, Center for Disease Control and Prevention, Public Health Service, U. S. Department of Health and Human Service, Fort Collins, Colorado

^* To whom correspondence should be addressed. Email: wwang60{at}yahoo.com.

	Abstract

Antibody response to the envelope (E) glycoprotein of dengue virus (DENV) is known to play a critical role in both protection and enhancement of disease, especially after primary infection. However, the relative amounts of homologous and heterologous anti-E antibodies and their epitopes remain unclear. In this study, we examined antibody responses to E protein as well as to precursor membrane (PrM), capsid and non-structural protein 1 (NS1) of four serotypes of DENV by Western blot analysis in DENV2 patients with different disease severity and immune status during an outbreak in southern Taiwan in 2002. Based on the early convalescent sera tested, the rates of antibody responses to PrM and NS1 proteins were significantly higher in patients with secondary infection than those with primary infection. Using a blocking experiment and neutralization assay, more than 90% of anti-E antibodies after primary infection were found to be cross-reactive and non-neutralizing against heterologous serotypes, and only a minor proportion was type-specific which may account for the type-specific neutralization activity. Moreover, the E-binding activity in sera of 10 patients with primary infection was greatly reduced by amino acid substitutions of three fusion loop residues, tryptophen at position 101, leucine at position 107 and phenylalanine at position 108, but not by those outside the fusion loop of domain II, suggesting that the predominantly cross-reactive anti-E antibodies recognized epitopes involving the highly conserved residues at the fusion loop of domain II. These findings have implications to our understanding of the pathogenesis of dengue and to future design of subunit vaccine against DENV as well.