The structural basis for serotype-specific neutralization of dengue virus by a human antibody

Ee Ping Teoh, Petra Kukkaro, En Wei Teo, Angeline P C Lim, Tze Tong Tan, Andy Yip, Wouter Schul, Myint Aung, Victor A. Kostyuchenko, Yee Sin Leo, Soh Ha Chan, Kenneth G C Smith, Annie Hoi Yi Chan, Gang Zou, Eng Eong Ooi, D. Michael Kemeny, Grace K. Tan, Jowin K W Ng, Mah Lee Ng, Sylvie Alonso & 5 others Dale Fisher, Pei-Yong Shi, Brendon J. Hanson, Shee Mei Lok, Paul A. MacAry

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

Dengue virus (DENV) is a mosquito-borne flavivirus that affects 2.5 billion people worldwide. There are four dengue serotypes (DENV1 to DENV4), and infection with one elicits lifelong immunity to that serotype but offers only transient protection against the other serotypes. Identification of the protective determinants of the human antibody response to DENV is a vital requirement for the design and evaluation of future preventative therapies and treatments. Here, we describe the isolation of a neutralizing antibody from a DENV1-infected patient. The human antibody 14c10 (HM14c10) binds specifically to DENV1. HM14c10 neutralizes the virus principally by blocking virus attachment; at higher concentrations, a post-attachment step can also be inhibited. In vivo studies show that the HM14c10 antibody has antiviral activity at picomolar concentrations. A 7 Å resolution cryoelectron microscopy map of Fab fragments of HM14c10 in a complex with DENV1 shows targeting of a discontinuous epitope that spans the adjacent surface of envelope protein dimers. As found previously, a human antibody specific for the related West Nile virus binds to a similar quaternary structure, suggesting that this could be an immunodominant epitope. These findings provide a structural and molecular context for durable, serotype-specific immunity to DENV infection.

Original languageEnglish (US)
Article number139ra83
JournalScience Translational Medicine
Volume4
Issue number139
DOIs
StatePublished - Jun 20 2012
Externally publishedYes

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Dengue Virus
Antibodies
Immunity
Cryoelectron Microscopy
Virus Attachment
Flavivirus
Immunodominant Epitopes
West Nile virus
Immunoglobulin Fab Fragments
Dengue
Virus Diseases
Neutralizing Antibodies
Culicidae
Antibody Formation
Antiviral Agents
Serogroup
Epitopes
Membrane Proteins
Viruses
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Teoh, E. P., Kukkaro, P., Teo, E. W., Lim, A. P. C., Tan, T. T., Yip, A., ... MacAry, P. A. (2012). The structural basis for serotype-specific neutralization of dengue virus by a human antibody. Science Translational Medicine, 4(139), [139ra83]. https://doi.org/10.1126/scitranslmed.3003888

The structural basis for serotype-specific neutralization of dengue virus by a human antibody. / Teoh, Ee Ping; Kukkaro, Petra; Teo, En Wei; Lim, Angeline P C; Tan, Tze Tong; Yip, Andy; Schul, Wouter; Aung, Myint; Kostyuchenko, Victor A.; Leo, Yee Sin; Chan, Soh Ha; Smith, Kenneth G C; Chan, Annie Hoi Yi; Zou, Gang; Ooi, Eng Eong; Kemeny, D. Michael; Tan, Grace K.; Ng, Jowin K W; Ng, Mah Lee; Alonso, Sylvie; Fisher, Dale; Shi, Pei-Yong; Hanson, Brendon J.; Lok, Shee Mei; MacAry, Paul A.

In: Science Translational Medicine, Vol. 4, No. 139, 139ra83, 20.06.2012.

Research output: Contribution to journalArticle

Teoh, EP, Kukkaro, P, Teo, EW, Lim, APC, Tan, TT, Yip, A, Schul, W, Aung, M, Kostyuchenko, VA, Leo, YS, Chan, SH, Smith, KGC, Chan, AHY, Zou, G, Ooi, EE, Kemeny, DM, Tan, GK, Ng, JKW, Ng, ML, Alonso, S, Fisher, D, Shi, P-Y, Hanson, BJ, Lok, SM & MacAry, PA 2012, 'The structural basis for serotype-specific neutralization of dengue virus by a human antibody', Science Translational Medicine, vol. 4, no. 139, 139ra83. https://doi.org/10.1126/scitranslmed.3003888
Teoh, Ee Ping ; Kukkaro, Petra ; Teo, En Wei ; Lim, Angeline P C ; Tan, Tze Tong ; Yip, Andy ; Schul, Wouter ; Aung, Myint ; Kostyuchenko, Victor A. ; Leo, Yee Sin ; Chan, Soh Ha ; Smith, Kenneth G C ; Chan, Annie Hoi Yi ; Zou, Gang ; Ooi, Eng Eong ; Kemeny, D. Michael ; Tan, Grace K. ; Ng, Jowin K W ; Ng, Mah Lee ; Alonso, Sylvie ; Fisher, Dale ; Shi, Pei-Yong ; Hanson, Brendon J. ; Lok, Shee Mei ; MacAry, Paul A. / The structural basis for serotype-specific neutralization of dengue virus by a human antibody. In: Science Translational Medicine. 2012 ; Vol. 4, No. 139.
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