Cryo-EM structure of an antibody that neutralizes dengue virus type 2 by locking E protein dimers

Guntur Fibriansah,1,2 Kristie D. Ibarra,3 Thiam-Seng Ng,1,2 Scott A. Smith,4,5

Joanne L. Tan,1,2 Xin-Ni Lim,1,2 Justin S. G. Ooi,1,2 Victor A. Kostyuchenko,1,2

Jiaqi Wang,1,2 Aravinda M. de Silva,6 Eva Harris,3

James E. Crowe Jr.,5,7* Shee-Mei Lok1,2*

SCIENCE RESEARCH | REPORTS 3 JULY 2015 • VOL 349 ISSUE 6243

Speaker: Shih-Chuan Li (李世詮)                                        Time: 15:00~16:00, Sep 30, 2015

Commentator: Dr. Shang-Rung Wu (吳尚蓉 博士)            Place: Room 601

Abstract:

        Dengue virus (DENV) is one of the most common Arbovirus, especially wild spread at east south Asia country. In Taiwan, it is estimated about over 15000 clinical cases this year. There are four dengue virus serotypes (from 1 to 4). When Infected with one serotype might generates antibodies that cross-react and enhance infection with other serotypes in a secondary infection. This effect is call antibody dependent enhancement (ADE) (1). The researchers demonstrated that DENV serotype 2 (DENV2)–specific human monoclonal antibody (HMAb) 2D22 is therapeutic in a mouse model of antibody-enhanced severe dengue disease (2). They also determined that the cryo–electron microscopy (cryo-EM) structures of HMAb 2D22 complexed with two different DENV2 strains that from lab or clinical strains. HMAb 2D22 is found to binds across viral envelope (E) proteins in the dimeric structure. The authors suggest this unique effect probably blocks the E protein reorganization required for virus fusion. By the researcher’s experiments and observation, HMAb 2D22 could “locks” two-thirds of or all dimers on the virus surface, depending on the strain. However, these DENV2 strains are neutralized with equal potency. The epitope defined by HMAb 2D22 would be a potential target for vaccines and therapeutics.

References:

1.     Scott B. Halstead (2003) neutralization and antibody-dependent enhancement of dengue viruses. Advances in virus research, VOL 60

2.     Ruklanthi de Alwis, Scott A. Smith, Nicholas P. Olivarez, William B. Messer, Jeremy P. Huynh, Wahala M. P. B. Wahala, Laura J. White , Michael S. Diamond, Ralph S. Baric, James E. Crowe, Jr., and Aravinda M. de Silva (2012) Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions. PNAS May 8, 2012 vol. 109 no. 19 7439–7444.