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

University of California Irvine, United States of America
PLoS Pathogens (Impact Factor: 7.56). 06/2008; 4(5):e1000060. DOI: 10.1371/journal.ppat.1000060
Source: PubMed


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.

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Available from: Christiane Jost
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    • "Additionally, the maturation state of virus particles can influence the capacity of antibodies to neutralize and enhance DENV infection (Nelson et al. 2008; Rodenhuis-Zybert et al. 2010, 2011b). Numerous studies have reported that anti-prM antibodies are commonly found in the sera of dengue-infected patients (Bray and Lai 1991; Cardosa et al. 2002; Se-Thoe et al. 1999) and the levels of prM antibodies were significantly higher in patients with secondary infection than sera from primary DENV infection (Lai et al. 2008), suggesting prM-specific antibodies play critical roles in human immune responses to DENV infection in both primary and secondary infection. "
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    ABSTRACT: Severe dengue is more likely found during secondary heterologous dengue virus (DENV) infection or primary infection of infants born to dengue-immune mothers and led to the hypothesis of antibody-dependent enhancement (ADE). It has been reported that pre-membrane (prM)-reactive antibodies do not efficiently neutralize DENV infection but instead potently promote ADE infection. Meanwhile, these enhancing anti-prM antibodies mainly react with the precursor (pr) peptide. To evaluate the effect of pr gene substitution on neutralization and ADE of DENV infection, a novel chimeric dengue virus (JEVpr/DENV2) was rationally constructed by replacing the DENV pr gene with Japanese encephalitis virus (JEV) pr gene, based on the full-length infectious complementary DNA (cDNA) clone of DENV2 ZS01/01. We found that chimeric JEVpr/DENV2 showed reduced virulence and good immunogenicity. In addition, anti-JEVpr/DENV2 sera showed broad cross-reactivity and efficient neutralizing activity with all four DENV serotypes and immature DENV2 (ImDENV2). Most importantly, compared with anti-DENV2 sera, anti-JEVpr/DENV2 sera showed significantly reduced enhancing activity of DENV infection in K562 cells. These results suggest that the ADE activities could be reduced by replacing the DENV pr gene with JEV pr gene. These findings may help us better understand the pathogenesis of DENV infection and provide a reference for the development of a vaccine against DENV.
    Full-text · Article · Jul 2015 · Applied Microbiology and Biotechnology
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    • "Early studies suggested that complete maturation is necessary to render flavivirus particles infectious (Stadler et al., 1997). However, recent studies have demonstrated that not only are virions retaining uncleaved prM infectious (Colpitts et al., 2011; Mukherjee et al., 2011; Nelson et al., 2008; Zybert et al., 2008), but that complete maturation may be detrimental to WNV replication under certain circumstances (Zybert et al., 2008). Whilst most strains of WNV contain a glycosylation site in both E and the precursor portion of prM, some non-pathogenic strains lack the E glycosylation site. "
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    • "Previous studies have demonstrated that mature particles and partially mature particles were infectious whereas immature particles were virtually non-infectious [24,27,42,56]. The maturation state of virus particles can influence the neutralizing and enhancing capacity of antibodies direct against DENV surface proteins [24,27,63]. We detected the specific infectivity of the LoVo-released virus particles and found that the infectious properties of imDENV2 was 10,000-fold lower compared to that of C6/36-cultured standard virus preparations. "
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