title: Antibodies against the envelope glycoprotein promote infectivity of immature dengue virus serotype 2.
abstract: Cross-reactive dengue virus (DENV) antibodies directed against the envelope (E) and precursor membrane (prM) proteins are believed to contribute to the development of severe dengue disease by facilitating antibody-dependent enhancement of infection. We and others recently demonstrated that anti-prM antibodies render essentially non-infectious immature DENV infectious in Fcγ-receptor-expressing cells. Immature DENV particles are abundantly present in standard (st) virus preparations due to inefficient processing of prM to M during virus maturation. Structural analysis has revealed that the E protein is exposed in immature particles and this prompted us to investigate whether antibodies to E render immature particles infectious. To this end, we analyzed the enhancing properties of 27 anti-E antibodies directed against distinct structural domains. Of these, 23 bound to immature particles, and 15 enhanced infectivity of immature DENV in a furin-dependent manner. The significance of these findings was subsequently tested in vivo using the well-established West Nile virus (WNV) mouse model. Remarkably, mice injected with immature WNV opsonized with anti-E mAbs or immune serum produced a lethal infection in a dose-dependent manner, whereas in the absence of antibody immature WNV virions caused no morbidity or mortality. Furthermore, enhancement infection studies with standard (st) DENV preparations opsonized with anti-E mAbs in the presence or absence of furin inhibitor revealed that prM-containing particles present within st virus preparations contribute to antibody-dependent enhancement of infection. Taken together, our results support the notion that antibodies against the structural proteins prM and E both can promote pathogenesis by enhancing infectivity of prM-containing immature and partially mature flavivirus particles.
authors.affiliation: Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
authors.forename: Júlia M
authors.initials: JM
authors.lastname: da Silva Voorham
authors.forename: Izabela A
authors.initials: IA
authors.lastname: Rodenhuis-Zybert
authors.forename: Nilda Vanesa
authors.initials: NV
authors.lastname: Ayala Nuñez
authors.forename: Tonya M
authors.initials: TM
authors.lastname: Colpitts
authors.forename: Heidi
authors.initials: H
authors.lastname: van der Ende-Metselaar
authors.forename: Erol
authors.initials: E
authors.lastname: Fikrig
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Jan
authors.initials: J
authors.lastname: Wilschut
authors.forename: Jolanda M
authors.initials: JM
authors.lastname: Smit
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology*; D019067:Antibody-Dependent Enhancement / Q000276:immunology; D002460:Cell Line; D003716:Dengue Virus / Q000145:classification / Q000276:immunology* / Q000472:pathogenicity*; D045683:Furin / Q000037:antagonists & inhibitors / Q000276:immunology; D007106:Immune Sera / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009895:Opsonin Proteins / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011498:Protein Precursors / Q000276:immunology; D012703:Serotyping; D014759:Viral Envelope Proteins / Q000276:immunology*; D014771:Virion / Q000276:immunology; D014901:West Nile Fever / Q000276:immunology / Q000821:virology; D014902:West Nile virus / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; C051821:E-glycoprotein, Dengue virus type 2; D007106:Immune Sera; D008565:Membrane Proteins; D009895:Opsonin Proteins; D011498:Protein Precursors; D014759:Viral Envelope Proteins; D045683:Furin