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

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.; Burton, Dennis R.

We designed an SIVcpzPtt-based disulfide (SOS), I559P (IP) prefusion stabilized Env ectodomain truncated as residue 664 (SOSIP.664) trimer, MT145K, that displays native trimer-like properties, and selectively binds V2-apex bnAbs as well as their germline reverted precursor versions. We determined a structure of the MT145K trimer by cryo-EM at a global resolution of 4.1 Ã… and the overall architecture was remarkably similar to HIV Env trimers (Julien et al., 2013a; Lyumkis et al., 2013; Ozorowski et al., 2017; Pancera et al., 2014) . In addition, the glycan shield composition of MT145K closely resembled that of HIV Env glycans but was sufficiently different in positioning of the glycans to exclude binding of all HIV bnAbs except for those directed to the V2-apex. MT145K trimer immunization in a V2-apex unmutated common ancestor (UCA)-expressing knockin mouse model revealed induction of a predominantly V2-apex neutralizing Ab response that was reproducible and cross-neutralized a related set of HIV isolates. Overall, the chimpanzee MT145K immunogen shows potential as an immunogen in HIV vaccination strategies.