Maturation of West Nile Virus Modulates Sensitivity to Antibody-Mediated Neutralization

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.

Nanobodies Targeting Norovirus Capsid Reveal Functional Epitopes and Potential Mechanisms of Neutralization

“…Internal plasticity and motions of the capsid proteins can allow access to buried regions, which often play an important role in the viral life cycle [46]. Indeed, multiple antibodies against picornaviruses and flaviviruses that bind to normally inaccessible sites on the viral capsid were shown to be highly neutralizing [47][48][49][50][51][52]. For rhinoviruses and polioviruses, buried regions of internal VP4 protein are transiently exposed due to the capsid "breathing" and are targeted by neutralizing mAbs.…”

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

“…Partially mature virions can be infectious, although the extent of prM cleavage required for infectivity is not known (reviewed in reference 39). The efficiency of virion maturation has the potential to impact virus binding, environmental conditions required to trigger membrane fusion, cellular tropism, and sensitivity to antibodymediated neutralization (40)(41)(42)(43)(44).…”

West Nile Virus: Basic Principles, Replication Mechanism, Immune Response and Important Genetic Determinants of Virulence

“…However, newer studies proved that even fully immature virions of flaviviruses can cause infection by antibodies [70,71]. Regarding partially immature virions, multiple studies have shown that they can also be infectious [17,72]. It seems that the mature part of these virions is responsible for cell binding and entry after which the further processing of remaining prM may take place inside the cell.…”

“…There are also many structurally distinct epitopes, not easily accessible to certain neutralizing antibodies. It is characteristic that studies showed a reduction of the neutralizing ability of antibodies correlated to the maturation state of WNV: Maturation reduces the accessibility of some of the epitopes on the virion [17]. Thus, these antibodies cannot efficiently neutralize the virus even if at high levels of concentration.…”

“…Mature virions are characterized by the structural change, rotation and rearrangement of the 60 trimeric prM-E heterodimers to form 90 antiparallel homodimers with quasi-icosahedral symmetry that cover the lipid membrane [15,16]. The E proteins are organized in 3 domains connected by flexible hinges [17]. Domain I (DI) is positioned at the central portion of the protein, linking together the other two domains.…”