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Journal of Virology, July 2008, p. 6631-6643, Vol. 82, No. 13
0022-538X/08/$08.00+0     doi:10.1128/JVI.00316-08
Copyright © 2008, American Society for Microbiology. 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

Chih-Yun Lai,^1, Wen-Yang Tsai,^1, Su-Ru Lin,¹ Chuan-Liang Kao,³ Hsien-Ping Hu,¹ Chwan-Chuen King,⁴ Han-Chung Wu,⁵ Gwong-Jen Chang,⁶ and Wei-Kung Wang^1,2*

Institute of Microbiology,¹ Department of Internal Medicine,² Institute of Medical Technology, College of Medicine,³ Institute of Epidemiology, College of Public Health, National Taiwan University,⁴ Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan,⁵ Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, U.S. Department of Health and Human Services, Fort Collins, Colorado⁶

Received 13 February 2008/ Accepted 14 April 2008

The antibody response to the envelope (E) glycoprotein of dengue virus (DENV) is known to play a critical role in both protection from 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 the antibody responses to E protein as well as to precursor membrane (PrM), capsid, and nonstructural protein 1 (NS1) of four serotypes of DENV by Western blot analysis of DENV serotype 2-infected patients with different disease severity and immune status during an outbreak in southern Taiwan in 2002. Based on the early-convalescent-phase sera tested, the rates of antibody responses to PrM and NS1 proteins were significantly higher in patients with secondary infection than in those with primary infection. A blocking experiment and neutralization assay showed that more than 90% of anti-E antibodies after primary infection were cross-reactive and nonneutralizing against heterologous serotypes and that only a minor proportion were 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 replacements of three fusion loop residues, tryptophan at position 101, leucine at position 107, and phenylalanine at position 108, but not by replacements of 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 for our understanding of the pathogenesis of dengue and for the future design of subunit vaccine against DENV as well.

Published ahead of print on 30 April 2008.

C.-Y.L. and W.-Y.T. contributed equally to the manuscript.