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 of the Env sites that has shown promise for vaccine targeting is the variable loop 2 (V2)-apex bnAb epitope (Andrabi et al., 2015; Gorman et al., 2016; Moore et al., 2017; Voss et al., 2017) . This bnAb epitope sits at the 3-fold axis of the trimer and is primarily formed by a patch rich in positively charged lysine residues and protected by two glycans at HXB2 HIV reference positions N160 and N156/N173 that are part of the Env glycan shield Bhiman et al., 2015; Bonsignori et al., 2011; Doria-Rose et al., 2014; Gorman et al., 2016; Julien et al., 2013b; Lee et al., 2017; McLellan et al., 2011; Pancera et al., 2013; Walker et al., 2009 Walker et al., , 2011 . The bnAb precursors targeting this site possess a long anionic heavy-chain complementarity-determining region 3 (CDRH3) that penetrates the glycan shield to reach the protein epitope surface underneath Doria-Rose et al., 2014; Landais et al., 2017; Lee et al., 2017; McLellan et al., 2011; Walker et al., 2009 Walker et al., , 2011 . BnAb prototypes within this class interact with the V2-apex bnAb protein-glycan core epitope through common germline-encoded motifs and are, thus, targetable by a small set of trimers that interact with germline-reverted V2-apex bnAbs, as previously reported by us and others (Andrabi et al., 2015; Gorman et al., 2016) . Hence, the germline-priming immunogens to this site could be based directly on native-like trimer configurations (Sanders et al., , 2015 . Other features that favor this site for vaccine targeting include the following: (1) V2-apex bnAbs are elicited frequently in humans that make bnAbs, (2) they emerge early in infection, and (3) they possess relatively low levels of somatic mutation compared to most other HIV Env bnAbs Doria-Rose et al., 2014; Georgiev et al., 2013; Kepler et al., 2014; Landais et al., 2016; Landais et al., 2017; Moore et al., 2011; Walker et al., 2009; Wibmer et al., 2013) .