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Journal of Virology, January 2008, p. 927-937, Vol. 82, No. 2
0022-538X/08/$08.00+0     doi:10.1128/JVI.00992-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Infection-Enhancing and -Neutralizing Activities of Mouse Monoclonal Antibodies against Dengue Type 2 and 4 Viruses Are Controlled by Complement Levels{triangledown}

Atsushi Yamanaka, Saori Kosugi, and Eiji Konishi*

Department of Health Sciences, Kobe University School of Medicine, 7-10-2, Tomogaoka, Suma-ku, Kobe 654-0142, Japan

Received 8 May 2007/ Accepted 24 October 2007

Dengue viruses are distributed widely in the tropical and subtropical areas of the world and cause dengue fever and its severer form, dengue hemorrhagic fever. While neutralizing antibodies are considered to play a major role in protection from these diseases, antibody-dependent enhancement (ADE) of infection is an important mechanism involved in disease severity, in addition to the involvement of T lymphocytes. Here, we analyzed relationships between neutralizing and enhancing activities at a clonal level using models of dengue type 2 virus (DENV2) and dengue type 4 virus (DENV4). Totals of 33 monoclonal antibodies (MAbs) against DENV2 and 43 against DENV4 were generated, all directed to the envelope protein. In these MAbs, enhancing activities were shown at subneutralizing doses under normal ADE assay conditions where test samples were heat inactivated. However, the inclusion of commercial rabbit complement or fresh sera from healthy humans in the ADE assay system abolished the enhancing activities of all these MAbs. The reductive effect of fresh sera on enhancing activities was significantly reduced by their heat inactivation or the use of C1q- or C3-depleted sera. In some fresh sera, enhancing activities were shown within a range of 20 to 80% of normal complement levels in a dose-dependent fashion. These results indicate that a single antibody species possesses two distinct activities (neutralizing/enhancing), which are controlled by the level of complement, suggesting the involvement of complement in dengue disease severity. Fresh human sera also tended to reduce enhancing activities more effectively in homologous than heterologous combinations of viruses (DENV2/DENV4) and MAbs (against DENV2/DENV4).

* Corresponding author. Mailing address: Department of Health Sciences, Kobe University School of Medicine, 7-10-2, Tomogaoka, Suma-ku, Kobe 654-0142, Japan. Phone and fax: 81-78-796-4594. E-mail: ekon{at}kobe-u.ac.jp

{triangledown} Published ahead of print on 14 November 2007.

Journal of Virology, January 2008, p. 927-937, Vol. 82, No. 2
0022-538X/08/$08.00+0     doi:10.1128/JVI.00992-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Martina, B. E. E., Koraka, P., Osterhaus, A. D. M. E. (2009). Dengue Virus Pathogenesis: an Integrated View. Clin. Microbiol. Rev. 22: 564-581 [Abstract] [Full Text]  


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