Molecular Simulations Reveal the Role of Antibody Fine Specificity and Viral Maturation State on Antibody-Dependent Enhancement of Infection in Dengue Virus.

Daniel R Ripoll,Anders Wallqvist,Sidhartha Chaudhury

doi:10.3389/fcimb.2019.00200

Abstract

Recent clinical studies have revealed that severe symptoms of dengue fever are associated with low pre-existing antibody levels. These findings provide direct clinical evidence for the theory of antibody-dependent enhancement of infection (ADE), which postulates that sub-neutralizing levels of antibodies facilitate the invasion of host cells by the dengue virus. Here, we carried out molecular simulations guided by previous in vitro experiments and structural studies to explore the role of antibody fine-specificity, viral conformation, and maturation state—key aspects of dengue virology that are difficult to manipulate experimentally—on ADE in the context of primary and secondary infections. Our simulation results reproduced in vitro studies of ADE, providing a molecular basis for how sub-neutralizing antibody concentrations can enhance infection. We found that antibody fine specificity, or the relative antibody response to different epitopes on the surface of the dengue virus, plays a major role in determining the degree of ADE observed at low antibody concentrations. Specifically, we found that the higher the relative antibody response to certain cross-reactive epitopes, such as the fusion loop or prM, the greater was the range of antibody concentrations where ADE occurred, providing a basis for why low antibody concentrations are associated with severe dengue disease in secondary infections. Furthermore, we found that partially mature viral states, in particular, are associated with the greatest degree of ADE.

Highlights

Dengue virus (DENV), a major human pathogen transmitted by Aedes aegypti mosquitoes, causes an estimated 390 million infections each year (Bhatt et al, 2013)
We carried out molecular simulations of polyclonal Abs binding to DENV, West Nile Virus (WNV), and Zika virus (ZIKV) virions to explore the contributions of Ab concentration, epitope fine specificity, and virus maturation state on infectivity and antibody-dependent enhancement of infection (ADE)
We considered a wide range of maturation states and ran the simulations with TS monoclonal Abs (mAbs) concentrations ranging from 10−1 to 10−14 M, assuming high binding affinity for the virion (KA = 10−9 M)

Summary

Introduction

Dengue virus (DENV), a major human pathogen transmitted by Aedes aegypti mosquitoes, causes an estimated 390 million infections each year (Bhatt et al, 2013). Whereas primary dengue infection is typically asymptomatic or results in a mild, uncomplicated fever, secondary infection with a heterotypic serotype is associated with severe disease manifestations, such as dengue hemorrhagic fever, and occasionally, death. Simulating ADE in Dengue Virus (Halstead, 1970; Sangkawibha et al, 1984; Guzman and Harris, 2015). This pattern of outcomes has led to the hypothesis that pre-existing immunity to DENV is responsible for enhanced secondary infections. Two clinical studies that assessed the longitudinal risk of severe dengue disease following primary and secondary infection found that low pre-existing serum concentrations of antibodies (Abs) to dengue virus were associated with the highest risk of severe symptoms. In a study of children in Nicaragua, Katzelnick et al (2017) found that individuals with pre-existing DENV Ab titers within a narrow intermediate range had the highest risk of severe symptoms, compared to those with high DENV Ab titers and those that were seronegative for DENV infection

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Conclusion