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Structures Of Respiratory Syncytial Virus G Antigen Bound To Broadly Neutralizing Antibodies For Vaccine And Therapeutic Design

  • Author(s): Fedechkin, Stanislav
  • Advisor(s): DuBois, Rebecca
  • et al.
Abstract

Respiratory syncytial virus (RSV) is a top cause of severe lower respiratory tract disease and mortality in young children and the elderly. The viral envelope G glycoprotein contributes to pathogenesis through its roles in host cell attachment and modulation of host immunity. Although the G glycoprotein is a target of protective RSV-neutralizing antibodies, its development as a vaccine antigen has been hindered by its heterogeneous glycosylation and sequence variability outside a conserved central domain (CCD). We describe the cocrystal structures of three high-affinity broadly neutralizing human monoclonal antibodies bound to the RSV G CCD. All three antibodies bind to conformational epitopes that span a highly conserved surface, illuminating an important region of vulnerability. We further show that isolated RSV G CCD activates the chemokine receptor CX3CR1 and that antibodies block this activity. These studies provide a template for rational vaccine design targeting this key contributor to RSV disease.

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