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.

Immunogen templates based on native-like Env trimers offer potential for HIV vaccine development, as they display bnAb epitopes and largely occlude non-native epitopes. However, it remains challenging to induce an epitope-focused bnAb response with Env trimer immunogens, as the bnAb epitopes are relatively immunoquiescent and even very limited exposure of non-desirable epitopes can negatively impact responses to bnAb epitopes (Havenar-Daughton et al., 2017; Wang et al., 2015) . Therefore, trimer designs and/or strategies that can mask non-relevant immunodominant epitopes or reduce induction of off-target Ab responses could help guide immunofocused neutralizing responses. In addition, the typical lack of interaction of Env forms with germline-reverted bnAb precursors means difficulties in activating the appropriate B cell lineages. Accordingly, we undertook design of a trimer immunogen that could help guide an epitope-focused Ab response to the V2-apex site of HIV Env. Based on previous studies, we hypothesized that a chimpanzee SIVcpzPtt/Pts or gorilla SIVgor Env sequence-based trimer that shares the V2-apex bnAb epitope with HIV could enrich B cell precursors and boost responses specific to this site (Barbian et al., 2015) . Since SIVcpzPtt, among various SIV-species Env sequences, are phylogenetically closest to the HIV Env, we surmised that the SOSIP.664 trimerstabilizing modifications, which have been used on several HIV Env backgrounds, may function in the stabilization of soluble SIV Env (Gao et al., 1999; Sanders et al., 2013; Sharp and Hahn, 2011) .