A Human Antibody Neutralizes Different Flaviviruses by Using Different Mechanisms

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Dengue virus (DENV) and Zika virus (ZIKV) are significant flaviviruses with distinct clinical manifestations.
• Understanding antibody neutralization mechanisms is crucial for developing effective antiviral therapies.

Purpose of the Study:

• To elucidate the differential neutralization mechanisms of human antibody SIgN-3C against DENV and ZIKV.
• To investigate the structural basis of SIgN-3C antibody interactions with DENV and ZIKV at various pH conditions.

Main Methods:

• Cryoelectron microscopy (cryo-EM) was used to determine the complex structures of antibody fragments (Fabs) with DENV and ZIKV.
• Experiments were conducted at extracellular (pH 8.0) and acidic endosomal (pH 8.0-5.0) conditions.

Main Results:

• SIgN-3C Fabs crosslink DENV and ZIKV E protein dimers at pH 8.0 and acidic conditions.
• Fab binding to DENV prevents virus fusion, with increased Fab numbers at lower pH.
• ZIKV structural changes at pH 5.0 were not inhibited despite high Fab density.
• Immunoglobulin G (IgG) interactions differed, with potential aggregation of DENV2:IgG complexes in endosomes.

Conclusions:

• The human antibody SIgN-3C employs distinct neutralization strategies against DENV and ZIKV.
• Structural differences in virus-antibody interactions, particularly at endosomal pH, dictate neutralization efficacy.
• Antibody behavior, including potential aggregation, varies significantly between DENV and ZIKV, impacting therapeutic potential.