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 cryo-EM structure of MT145K SOSIP trimer revealed that the Env trimers of HIV and chimpanzee SIV have very similar UCA HC-only KI mice with a chimpanzee SIV MT145K trimer followed by an HIV Env-derived three-trimer cocktail. A group of five animals was immunized with two doses (prime, week 0; boost-1, week 4) of the MT145K trimer (as also shown in Figure 6 ). The animals were further boosted (boost-2 at week 8) with an HIV Envderived three-trimer cocktail (C108, WITO, and ZM197-ZM233V1V2). The V1V2 loops on trimer cartoons are depicted in red to highlight that the region is shared between HIV and SIV Env trimers. The CH01 UCA HC-only KI mice were immunized with 25 mg of the soluble MT145K trimer or HIV three-trimer cocktail (25 mg total) with GLA-SE as adjuvant. Time points for the immunizations and the bleeds are indicated. (B) The ID50 virus neutralization titers of the Bleed #4 serum samples collected post boost-2 immunization with an HIV three-trimer cocktail. The neutralization of the post-immune sera was assessed against the priming immunogen-matched autologous virus, MT145K, the boosting immunogen-matched, CH01 sensitive viruses, and global panel HIV Env-encoding viruses. Each filled circle in the plot represents virus ID50 neutralization values for the individual animals; an asterisk (*) indicates that 50% neutralization was not reached at a 1:100 serum dilution. overall architectures. The glycan shield of chimpanzee SIV forms a similarly dense protective layer to antibody recognition of the protein surface as observed in HIV. However, subtle movements in the locations of the glycans appear to contribute to the inability of the great majority of HIV bnAbs to recognize the chimpanzee SIV Env trimer. As noted above, bnAbs to the V2-apex region of the trimer are the exception. We have hypothesized previously that the conservation of this region among HIV isolates is to facilitate trimer disassembly during viral entry. It is interesting that the overall V2-apex structure is conserved across the chimpanzee-human species barrier, indicating its critical importance for Env function.