Andrabi, Raiees, Pallesen, Jesper, Allen, Joel D., Song, Ge, Zhang, Jinsong, de Val, Natalia, Gegg, Gavin, Porter, Katelyn, Su, Ching Yao, Pauthner, Matthias, Newman, Amanda, Bouton-Verville, Hilary, Garces, Fernando, Wilson, Ian A., Crispin, Max, Hahn, Beatrice H., Haynes, Barton F., Verkoczy, Laurent, Ward, Andrew B. and Burton, Dennis R. (2019) The chimpanzee SIV envelope trimer: Structure and deployment as an HIV vaccine template. Cell Reports, 27 (8), 2426-2441.e6. (doi:10.1016/j.celrep.2019.04.082).
Abstract
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.
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