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 CD4bs is conserved between HIV and SIV to the extent that there is cross-species reactivity with sCD4. Human CD4-IgG2 immunoadhesin showed strong binding to the MT145K trimer, indicating a strong cross-species conservation of the Env CD4bs. Phe43 in domain-1 of human sCD4 would fit well inside the Trp427 Env cavity on the MT145K trimer, reminiscent of its interaction with the HIV Env BG505 trimer ( Figure 5D ) . However, the MT145K trimer is non-reactive with CD4bs bnAbs. VRC01, one of the bnAbs in this class, binds to the HIV Env CD4bs bnAb epitope formed by discontinuous protein backbone elements including loop D of the gp120-C2 region and bordered by a glycan at N276 (Figures 5E, 5F , S5, and S8) . MT145K lacks the N276 glycan and the proximal N234 glycan, present in most HIV Envs, but instead has a glycan at position 236. Differences in the loop D sequence ( Figure S5 ) and the glycan at N236, which may clash with VRC01 CDRL1 and CDRL3 loops ( Figure 5F ), on the MT145K trimer likely impose the biggest impediment to VRC01 binding. Further, the MT145K gp120-V5 loop has a six-amino-acid insertion at HXB2 position 456 compared to HIV Envs that may clash with the VRC01 LC ( Figures 5F and S5) .