Partial maturation: an immune-evasion strategy of dengue virus?

Rodenhuis-Zybert, Izabela A.; Wilschut, Jan; Smit, Jolanda M.

doi:10.1016/j.tim.2011.02.002

Cited by 53 publications

(64 citation statements)

References 78 publications

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“…Thus, it appears that the N67 and N153 glycosylation sites in DENV E are utilized to differing degrees, and the glycans positioned at each site are differentially matured. Considering that structural studies of DENV prM and E have demonstrated partial occlusion of one or both E glycans by the pr peptide Yu et al, 2008), and that DENV has a demonstrated tendency towards incomplete prM cleavage by furin (Rodenhuis-Zybert et al, 2011), these results raise the interesting possibility that the degree of prM processing controls the maturation status of one or both glycans. Such a hypothesis remains to be properly explored, although it would be intriguing to investigate whether partially matured DENV displays a greater capacity to infect DC-SIGN-expressing cells.…”

Section: Glycan Modificationmentioning

confidence: 90%

“…This phenomenon appears to be dependent upon the identity of the virus, as high rates of immature/partially mature virions are most consistently observed for DENV (Rodenhuis-Zybert et al, 2011), and this phenotype has been linked to a DENV-conserved acidic residue at position 89 in prM (P3 within the furin cleavage site) (Junjhon et al, 2008;Keelapang et al, 2004). WNV and TBEV grown in BHK-21 cells have similarly been identified as partially incomplete in maturity, with faint staining of uncleaved prM in immunoblots prepared with purified virus (Elshuber & Mandl, 2005;Moesker et al, 2010), although complete prM cleavage has also been observed with TBEV in this same cell line (Stadler et al, 1997).…”

Section: Maturation Of Prm By Furin Cleavagementioning

confidence: 99%

“…Bound virions are endocytosed, with acidification of the endosome allowing furin-mediated cleavage of prM and subsequent virus fusion. The identification of this prM antibody-enhanced infection process has led researchers to postulate that this phenomenon may allow a degree of escape from the neutralizing host anti-E antibody response (reviewed by Rodenhuis-Zybert et al, 2011) and may inform the design of better vaccines (see below). The role that immature/partially mature DENV virions play during infection of Aedes spp.…”

Section: Maturation Of Prm By Furin Cleavagementioning

confidence: 99%

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Post-translational regulation and modifications of flavivirus structural proteins

Roby

Setoh

Hall

et al. 2015

Journal of General Virology

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Flaviviruses are a group of single-stranded, positive-sense RNA viruses that generally circulate between arthropod vectors and susceptible vertebrate hosts, producing significant human and veterinary disease burdens. Intensive research efforts have broadened our scientific understanding of the replication cycles of these viruses and have revealed several elegant and tightly co-ordinated post-translational modifications that regulate the activity of viral proteins. The three structural proteins in particular -capsid (C), pre-membrane (prM) and envelope (E) -are subjected to strict regulatory modifications as they progress from translation through virus particle assembly and egress. The timing of proteolytic cleavage events at the C-prM junction directly influences the degree of genomic RNA packaging into nascent virions. Proteolytic maturation of prM by host furin during Golgi transit facilitates rearrangement of the E proteins at the virion surface, exposing the fusion loop and thus increasing particle infectivity. Specific interactions between the prM and E proteins are also important for particle assembly, as prM acts as a chaperone, facilitating correct conformational folding of E. It is only once prM/E heterodimers form that these proteins can be secreted efficiently. The addition of branched glycans to the prM and E proteins during virion transit also plays a key role in modulating the rate of secretion, pH sensitivity and infectivity of flavivirus particles. The insights gained from research into post-translational regulation of structural proteins are beginning to be applied in the rational design of improved flavivirus vaccine candidates and make attractive targets for the development of novel therapeutics. FlavivirusesThe genus Flavivirus in the family Flaviviridae comprises small, enveloped viruses with non-segmented genomes consisting of single-stranded, positive-sense RNA. These RNA genomes are flanked by 59 and 39 untranslated regions (UTRs) and encode a single polyprotein that is cleaved coand post-translationally to generate between 10 and 11 viral proteins. The 59 UTR contains a type 1 m 7 GpppNm cap structure and the 39 UTR lacks a polyadenylated tail. Structural elements within the UTRs regulate genome replication, translation and host immune responses. Viral proteins are divided between structural proteins, which form the virion, and non-structural proteins, which are involved in genomic replication and modulating host immunity (Fig. 1a) (Lindenbach et al., 2007;Roby et al., 2012).Flaviviruses are maintained predominantly in natural transmission cycles between vertebrate reservoir species (normally mammalian or avian) and haematophagous arthropod vectors (mosquitoes or ticks). Notable exceptions are the viruses that are maintained solely in mosquito hosts (insectspecific flaviviruses) and viruses with no known invertebrate vector (Cook et al., 2012;Mackenzie et al., 2004). As of 2013, the International Committee on Taxonomy of Viruses has classified 53 different viral species as belonging to ...

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Section: Glycan Modificationmentioning

confidence: 90%

Section: Maturation Of Prm By Furin Cleavagementioning

confidence: 99%

Section: Maturation Of Prm By Furin Cleavagementioning

confidence: 99%

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Post-translational regulation and modifications of flavivirus structural proteins

Roby

Setoh

Hall

et al. 2015

Journal of General Virology

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“…It is known that in the case of flaviviruses (35), in vivo capsid maturation is driven by pH acidification. For these viruses, immature capsids are assembled at the endoplasmic reticulum (pH 7.2) and are transported through the secretory pathway to the trans-Golgi network, where maturation occurs upon pH lowering (pH 5.7) (35).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Quantification of the Relative Packaging Efficiencies of Single-Stranded RNA Molecules by Viral Capsid Protein

Comas-García

Cadena-Nava

Rao

et al. 2012

J Virol

113

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While most T‫3؍‬ single-stranded RNA (ssRNA) viruses package in vivo about 3,000 nucleotides (nt), in vitro experiments have demonstrated that a broad range of RNA lengths can be packaged. Under the right solution conditions, for example, cowpea chlorotic mottle virus (CCMV) capsid protein (CP) has been shown to package RNA molecules whose lengths range from 100 to 10,000 nt. Furthermore, in each case it can package the RNA completely, as long as the mass ratio of CP to nucleic acid in the assembly mixture is 6:1 or higher. Yet the packaging efficiencies of the RNAs can differ widely, as we demonstrate by measurements in which two RNAs compete head-to-head for a limited amount of CP. We show that the relative efficiency depends nonmonotonically on the RNA length, with 3,200 nt being optimum for packaging by the T‫3؍‬ capsids preferred by CCMV CP. When two RNAs of the same length-and hence the same charge-compete for CP, differences in packaging efficiency are necessarily due to differences in their secondary structures and/or three-dimensional (3D) sizes. For example, the heterologous RNA1 of brome mosaic virus (BMV) is packaged three times more efficiently by CCMV CP than is RNA1 of CCMV, even though the two RNAs have virtually identical lengths. Finally, we show that in an assembly mixture at neutral pH, CP binds reversibly to the RNA and there is a reversible equilibrium between all the various RNA/CP complexes. At acidic pH, excess protein unbinds from RNA/CP complexes and nucleocapsids form irreversibly.T he remarkable capacity of the capsid protein (CP) of cowpea chlorotic mottle virus (CCMV) to self-assemble in vitro into nanometer-size capsids around a broad range of anionic materials-its own single-stranded RNA (ssRNA) genome (2, 6), heterologous ssRNAs (3,4,9,24), organic polymers such as polystyrene sulfonate (11,16,23), metal oxide particles (19, 28), functionalized gold nanoparticles (5), and negatively charged nanoemulsion droplets (13)-as well as into a wide range of structures in the absence of any polyanions (1,8,26) has spurred interest in the mechanism of assembly. But a fundamental question has rarely or only inadequately been addressed: how efficient are the assembly processes?To answer this question, it is first necessary to formulate a precise definition of efficiency of assembly, along with a procedure for determining it. In some cases, efficiency has been quantified as the fraction of filled capsids in the mixture of filled and empty capsids observed in electron micrographs of the assembly mixture (14), but this depends on the formation of empty capsids under the conditions of filled-capsid assembly. In other cases, the relative efficiency of packaging an RNA molecule has been defined as the ratio of the number of in vivo capsids containing it to the number formed with the genomic RNA (5), when both are present in the same CP-expressing cell; however, this requires additional knowledge about the relative levels of replication of both RNAs.Several assembly experiments, both in vivo and in...

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“…An additional mechanism of ADE has been demonstrated to occur with anti-prM antibodies. Using either mouse or human MAbs, investigators have shown that the presence of anti-prM antibodies causes immature viral particles that have prM on the surface, which are normally noninfectious, to acquire the ability to infect cells efficiently through Fc-mediated pathways (8,40,41). The role that ADE plays in the pathogenesis of DENV infection is of significant interest.…”

mentioning

confidence: 99%

Persistence of Circulating Memory B Cell Clones with Potential for Dengue Virus Disease Enhancement for Decades following Infection

Smith

Zhou

Olivarez

et al. 2012

J Virol

137

173

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Symptomatic dengue virus infection ranges in disease severity from an influenza-like illness to life-threatening shock. One model of the mechanism underlying severe disease proposes that weakly neutralizing, dengue serotype cross-reactive antibodies induced during a primary infection facilitate virus entry into Fc receptor-bearing cells during a subsequent secondary infection, increasing viral replication and the release of cytokines and vasoactive mediators, culminating in shock. This process has been termed antibody-dependent enhancement of infection and has significantly hindered vaccine development. Much of our understanding of this process has come from studies using mouse monoclonal antibodies (MAbs); however, antibody responses in mice typically exhibit less complexity than those in humans. A better understanding of the humoral immune response to natural dengue virus infection in humans is sorely needed. Using a high-efficiency human hybridoma technology, we isolated 37 hybridomas secreting human MAbs to dengue viruses from 12 subjects years or even decades following primary or secondary infection. The majority of the human antibodies recovered were broadly cross-reactive, directed against either envelope or premembrane proteins, and capable of enhancement of infection in vitro; few exhibited serotype-specific binding or potent neutralizing activity. Memory B cells encoding enhancing antibodies predominated in the circulation, even two or more decades following infection. Mapping the epitopes and activity of naturally occurring dengue antibodies should prove valuable in determining whether the enhancing and neutralizing activity of antibodies can be separated. Such principles could be used in the rational design of vaccines that enhance the induction of neutralizing antibodies, while lowering the risk of dengue shock syndrome. D engue viruses (DENV) are expanding globally with an estimated 50 to 100 million cases of DENV infection occurring worldwide annually, and more than 20,000 associated deaths. It is now estimated that approximately one-fifth of the world population is at risk of infection by DENV (9, 12, 13). Dengue is also threatening the continental United States. More than 25 cases of locally acquired infection were reported in Key West, Florida, in 2009 and 2010 (1). Symptomatic dengue disease ranges in severity from an influenza-like illness to life-threatening hemorrhagic fever or shock. Understanding the pathogenesis of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is of central importance in the rational development of antiviral for treatment and vaccines to prevent dengue disease (11,49).The DENV complex consists of four serotypes. Infection with a single serotype leads to antibody responses that cross-react with all serotypes (14). Despite the cross-reactivity, individuals only develop protective immunity against the serotype responsible for infection (14,43). Human studies have established clearly that the risk of progressing to DHF is greater during secondary than during prim...

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Partial maturation: an immune-evasion strategy of dengue virus?

Cited by 53 publications

References 78 publications

Post-translational regulation and modifications of flavivirus structural proteins

Post-translational regulation and modifications of flavivirus structural proteins

In Vitro Quantification of the Relative Packaging Efficiencies of Single-Stranded RNA Molecules by Viral Capsid Protein

Persistence of Circulating Memory B Cell Clones with Potential for Dengue Virus Disease Enhancement for Decades following Infection

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