Abstract
Humoral immunity plays an important role in controlling dengue virus (DENV) infection. Antibodies (Abs) developed during primary infection protect against subsequent infection with the same dengue serotype, but can enhance disease following secondary infection with a heterologous serotype. A DENV virion has two surface proteins, envelope protein E and (pre)-membrane protein (pr)M, and inefficient cleavage of the prM protein during maturation of progeny virions leads to the secretion of immature and partially immature particles. Interestingly, we and others found that historically regarded non-infectious prM-containing DENV particles can become highly infectious in the presence of E- and prM-Abs. Accordingly, we hypothesized that these virions contribute to the exacerbation of disease during secondary infection. Here, we tested this hypothesis and investigated the ability of acute sera of 30 DENV2-infected patients with different grades of disease severity, to bind, neutralize and/or enhance immature DENV2. We found that a significant fraction of serum Abs bind to the prM protein and to immature virions, but we observed no significant difference between the disease severity groups. Furthermore, functional analysis of the Abs did not underscore any specific correlation between the neutralizing/enhancing activity towards immature DENV2 and the development of more severe disease. Based on our analysis of acute sera, we conclude that Abs binding to immature virions are not a discriminating factor in dengue pathogenesis.
Highlights
The four serotypes of dengue virus (DENV1–4) currently represent the most prevalent mosquito-borne viral disease of humans
Symptomatic infection can manifest itself as a selflimiting febrile illness, dengue fever (DF), or as more severe and potentially life-threatening dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS)
We analyzed the ability of acute sera of DF, DHF and DSS patients to bind, neutralize and/or enhance immature DENV infection
Summary
The four serotypes of dengue virus (DENV1–4) currently represent the most prevalent mosquito-borne viral disease of humans. Pathogenesis of DENV infection is multifaceted [5], but sequential infection with a heterologous DENV serotype as well as primary infection of infants born to dengue-immune mothers are known risk factors for severe disease. In ADE, cross-reactive, non-neutralizing Abs facilitate successful entry of virus-immune complexes into Fcγ-receptor-bearing cells [6,7,8] leading to an increased viral load early in infection [9, 10] and to the exacerbation of disease [11]. ADE of DENV infection can be observed in many Fc-receptor-expressing cell lines, including K562, U937, P388D1 and in primary human cells such as monocytes, macrophages and mature dendritic cells [6, 12, 13]
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