Under acidic conditions in the trans-Golgi, processed prM remains associated to the virion keeping E from undergoing fusogenic conformational changes. Under the acidic conditions of the trans-Golgi network, prM is cleaved by furin-like proteases, allowing E to dimerize, resulting in a mature virus particle and priming the metastable E dimers to undergo a pH-dependent transition to E trimers required for fusion during viral entry (Bressanelli et al. The prM-E heterodimers interact with capsid to form an immature particle, which buds into the lumen of the endoplasmic reticulum (Mukhopadhyay et al. In early stages of processing, E is present as a prM-E precursor (Li et al. The receptor binding sites are presumed to be located on EDIII (Modis et al. EDII bears the fusion loop peptide, which is buried at the dimer interface. EDI is a β barrel that extends into the finger-like EDII domain. A stem region connects the ectodomain (EDI-DIII) with the transmembrane domain. E proteins are transmembrane proteins of which the ectodomain is classified into three distinct domains, EDI, EDII, EDIII (Fig. On a fully mature particle, E proteins are present as 90 head-to-tail homodimers and units of three homodimers are organized as 30 herringbone raft-like structures that lie flat on the particle surface (Fig. The nucleocapsid is tightly surrounded by a host-derived lipid-bilayer envelope that anchors 180 copies of the E protein. Upon translation, capsid organizes into nucleocapsids that encapsulate the progeny viral RNA genome. DENV particles are composed of three structural proteins-capsid, pre-membrane (prM) and envelope (E). Non-neutralizing but serotype cross-reactive antibodies induced after primary infections can enhance secondary flavivirus infections by enabling virus entry through Fcγ-receptor-mediated endocytosis (Halstead and O'Rourke 1977 Guzman and Harris 2015). After primary exposure, people are more susceptible to severe and potentially fatal dengue hemorrhagic fever and dengue shock syndrome during secondary heterotypic infections, which is associated with antibody dependent enhancement (ADE). Primary infection results in specific long-term immunity to the serotype of infection, but individuals remain susceptible to any of the other three serotypes. Infections are often clinically inapparent, but when symptoms do arise, most patients suffer from a sudden onset of fever, skin rash, arthralgia and myalgia (Guzman and Harris 2015). The DENV family consists of four antigenically distinct serotypes, DENV1-4. These numbers are expected to grow due to viral evolution, expansion of the mosquito vector caused by climate change, the expansion of urban environments, and the increase of international travel and trade. Roughly 1 million infections develop into severe disease, of which 2%–5% are fatal (Bhatt et al. DENV represents a global threat to public health with over 390 million reported infections yearly in over 120 countries. Virology, dengue virus, subunit vaccine, quaternary epitopes, dimer, envelope protein INTRODUCTION Dengue virologyĭengue virus (DENV) is a member of the flaviviridae family and is the most prevalent arthropod-borne viral pathogen. In this review, we will address the shortcomings of recombinant E-based antigens and will discuss potential solutions to enhance E-based subunit antigen immunogenicity and vaccine efficacy. However, E-based subunits require further development and characterization to be used as effective vaccine antigens against DENV. So far, live-virus particle-based vaccine approaches struggle with inducing protective tetravalent immunity, while recombinant subunit approaches that use the envelope protein (E) as the major antigen, are gaining promise in preclinical studies. Development of a safe and efficacious DENV vaccine is challenging because of the need to induce immunity against all four serotypes simultaneously, as immunity against one serotype can potentially enhance disease caused by a heterotypic secondary infection. These viruses present a major global health burden, being endemic in over 120 countries, causing ∼390 million reported infections yearly, with clinical symptoms ranging from mild fever to severe and potentially fatal hemorrhagic syndromes. The four DENV serotypes are mosquito-borne pathogens that belong to the Flavivirus genus.
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