Antibodies against the envelope glycoprotein promote infectivity of immature dengue virus serotype 2

PLoS One. 2012;7(3):e29957. doi: 10.1371/journal.pone.0029957. Epub 2012 Mar 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Viral / immunology*
  • Antibody-Dependent Enhancement / immunology
  • Cell Line
  • Dengue Virus / classification
  • Dengue Virus / immunology*
  • Dengue Virus / pathogenicity*
  • Furin / antagonists & inhibitors
  • Furin / immunology
  • Immune Sera / immunology
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Opsonin Proteins / immunology
  • Protein Binding / immunology
  • Protein Precursors / immunology
  • Serotyping
  • Viral Envelope Proteins / immunology*
  • Virion / immunology
  • West Nile Fever / immunology
  • West Nile Fever / virology
  • West Nile virus / immunology

Substances

  • Antibodies, Monoclonal
  • Antibodies, Viral
  • E-glycoprotein, Dengue virus type 2
  • Immune Sera
  • Membrane Proteins
  • Opsonin Proteins
  • Protein Precursors
  • Viral Envelope Proteins
  • Furin