Abstract
West Nile virions incorporate 180 envelope (E) proteins that orchestrate the process of virus entry and are the primary target of neutralizing antibodies. The E proteins of newly synthesized West Nile virus (WNV) are organized into trimeric spikes composed of pre-membrane (prM) and E protein heterodimers. During egress, immature virions undergo a protease-mediated cleavage of prM that results in a reorganization of E protein into the pseudo-icosahedral arrangement characteristic of mature virions. While cleavage of prM is a required step in the virus life cycle, complete maturation is not required for infectivity and infectious virions may be heterogeneous with respect to the extent of prM cleavage. In this study, we demonstrate that virion maturation impacts the sensitivity of WNV to antibody-mediated neutralization. Complete maturation results in a significant reduction in sensitivity to neutralization by antibodies specific for poorly accessible epitopes that comprise a major component of the human antibody response following WNV infection or vaccination. This reduction in neutralization sensitivity reflects a decrease in the accessibility of epitopes on virions to levels that fall below a threshold required for neutralization. Thus, in addition to a role in facilitating viral entry, changes in E protein arrangement associated with maturation modulate neutralization sensitivity and introduce an additional layer of complexity into humoral immunity against WNV.
Highlights
Flaviviruses are a group of positive-stranded RNA viruses that are of global significance due to their widespread distribution and their ability to cause a variety of diseases in humans [1]
To investigate mechanisms that govern the potency of antibodies that target poorly accessible epitopes, high-resolution neutralization profiles were generated for a group of antibodies that recognize structurally distinct epitopes on the West Nile virus (WNV) E protein [17,18] (Fig. S1)
Dose-response curves obtained with the Domain III (DIII)-lr-specific Monoclonal antibodies (mAbs) E16 were sigmoidal, relatively steep, and revealed complete neutralization of WNV reporter virus particles (RVPs) at low concentrations of antibody (Fig. 1a; EC50 0.043 nM) [23]
Summary
Flaviviruses are a group of positive-stranded RNA viruses that are of global significance due to their widespread distribution and their ability to cause a variety of diseases in humans [1]. West Nile virus (WNV) is a mosquito-borne member of this genus and is the etiologic agent of West Nile encephalitis. WNV is endemic in parts of Africa, Australia, Europe, Asia, and the Middle East and has been responsible for periodic outbreaks of encephalitis in humans and horses. The introduction of WNV into North America in 1999 and its rapid spread across the United States into Canada, Mexico, and the Caribbean identifies this virus as an emerging pathogen of clinical and economic significance for the Western Hemisphere (reviewed in [2]). While seroprevalence studies indicate that most WNV infections of humans are subclinical, clinically apparent infections range from a febrile illness (West Nile fever) to more severe and potentially fatal neurologic disease [3]. No WNV vaccine has been approved for use in humans and treatment is supportive
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