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.

The immunogen-specific titers of the serum Ab responses post-prime immunizations (Bleed #1 samples) marginally increased in the MT145K group but remained largely unchanged in the MT145-WT trimer immunized group. The serum Ab titers post-boost-1 immunization (Bleed #2) increased in both the groups and were orders of magnitude higher as compared to the pre-bleed or the post-prime Ab binding responses ( Figure 6B ). At this immunization step, the serum Ab responses in the MT145K trimer immunized group were solely dependent on the N160 glycan while those in the MT145-WT trimer immunization group were mostly independent of the N160 glycan ( Figure 6B ). Therefore, we conclude that the engineered MT145K trimer, but not the MT145-WT, efficiently triggers the epitope-specific V2-apex bnAb UCA encoding B cell precursors in vivo. Remarkably, immunizations with the Q171K-substituted engineered MT145K trimer also appeared to eliminate the non-V2-apex bnAb site Envspecific off-target B cell responses that were elicited in the MT145-WT trimer immunization group ( Figure 6B ). The results demonstrate that the activation of the HIV Env bnAb-encoding un-mutated B cell precursor by immunogens that display binding to their UCA Ab versions is critical for eliciting epitope-specific Ab responses and the findings are consistent with studies that specifically use germline-targeting immunogen molecules to kick off the bnAb precursor encoding B cell responses in vivo (Dosenovic et al., 2015; Escolano et al., 2016; Jardine et al., 2015; McGuire et al., 2013; Sok et al., 2016a; Steichen et al., 2016; Tian et al., 2016) .