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.

One property thought to be critical for vaccine immunogens to select rare bnAb precursors is the ability to effectively bind to UCA B cell receptors (Dosenovic et al., 2015; Escolano et al., 2016; Jardine et al., 2015; McGuire et al., 2016; Steichen et al., 2016) . Therefore, to gain or improve binding of the V2-apex bnAb inferred precursor Abs to the MT145 Env trimer, we substituted a glutamine (Q) with a lysine (K) residue (HXB2 position 171) in strand C of the V2-apex bnAb core epitope ( Figures 1A and 1B) . We based this substitution on the presence of a positively charged motif (KKKK) in CRF250 and CP256.SU strand C V2 Env sequences, both of which bind V2-apex bnAb prototype precursors (Andrabi et al., 2015; Bhiman et al., 2015; Doria-Rose et al., 2014; Gorman et al., 2016) . ELISA binding revealed strong binding of the mature V2-apex bnAb prototypes with the MT145-WT trimer and weak but detectable binding with one of the UCA Abs, CAP256 UCA ( Figure 1C ). Strikingly, binding with our V2-engineered MT145 trimer (henceforth referred to as MT145K) not only improved binding to CAP256 UCA Ab but also conferred binding on both PG9 and CH01 inferred germ-line-reverted (iGL) Abs ( Figure 1C ). The PG9 and CH01 iGL Abs used here had diversity (D; heavy chain) and joining (J; both heavy and light chains) genes reverted to their corresponding germline gene families in the CDRH3s, in addition to the VH and VL regions reported previously (Andrabi et al., 2015; Gorman et al., 2016) .