Cell Reports (May 2019)

The Chimpanzee SIV Envelope Trimer: Structure and Deployment as an HIV Vaccine Template

  • Raiees Andrabi,
  • Jesper Pallesen,
  • Joel D. Allen,
  • Ge Song,
  • Jinsong Zhang,
  • Natalia de Val,
  • Gavin Gegg,
  • Katelyn Porter,
  • Ching-Yao Su,
  • Matthias Pauthner,
  • Amanda Newman,
  • Hilary Bouton-Verville,
  • Fernando Garces,
  • Ian A. Wilson,
  • Max Crispin,
  • Beatrice H. Hahn,
  • Barton F. Haynes,
  • Laurent Verkoczy,
  • Andrew B. Ward,
  • Dennis R. Burton

Journal volume & issue
Vol. 27, no. 8
pp. 2426 – 2441.e6

Abstract

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Summary: Epitope-targeted HIV vaccine design seeks to focus antibody responses to broadly neutralizing antibody (bnAb) sites by sequential immunization. A chimpanzee simian immunodeficiency virus (SIV) envelope (Env) shares a single bnAb site, the variable loop 2 (V2)-apex, with HIV, suggesting its possible utility in an HIV immunization strategy. Here, we generate a chimpanzee SIV Env trimer, MT145K, which displays selective binding to HIV V2-apex bnAbs and precursor versions, but no binding to other HIV specificities. We determine the structure of the MT145K trimer by cryo-EM and show that its architecture is remarkably similar to HIV Env. Immunization of an HIV V2-apex bnAb precursor Ab-expressing knockin mouse with the chimpanzee MT145K trimer induces HIV V2-specific neutralizing responses. Subsequent boosting with an HIV trimer cocktail induces responses that exhibit some virus cross-neutralization. Overall, the chimpanzee MT145K trimer behaves as expected from design both in vitro and in vivo and is an attractive potential component of a sequential immunization regimen to induce V2-apex bnAbs. : Design of immunogens and strategies that can induce protective broadly neutralizing antibodies (bnAbs) is a priority for HIV vaccine development. Andrabi et al. design a chimpanzee simian immunodeficiency virus (SIV) envelope trimer immunogen that binds specifically to HIV V2-apex bnAbs and their unmutated versions. The SIV trimer immunogen induces HIV-specific neutralizing antibodies (nAbs) in a favorable animal model. Keywords: human immunodeficiency virus, simian immunodeficiency virus, broadly neutralizing antibodies, HIV envelope trimer, chimpanzee SIV envelope trimer, glycan shield, V2-apex bnAb site, immunization strategies, HIV vaccine