Cell Rep. 2018 Sep 18; 24(12):3324-3338.e5.

PubMed ID: 30232012

Rational design of DNA-expressed stabilized native-like HIV-1 envelope trimers

Aldon Y, McKay PF, Allen J, Ozorowski G, Felfodine Levai R, Tolazzi M, Rogers P, He L, de Val N, Fabian K, Scarlatti G, Zhu J, Ward AB, Crispin M, Shattock RJ

The HIV-1-envelope glycoprotein (Env) is the main target of antigen design for antibody-based prophylactic vaccines. The generation of broadly neutralizing antibodies (bNAb) likely requires the appropriate presentation of stabilized trimers preventing exposure of non-neutralizing antibody (nNAb) epitopes. We designed a series of membrane-bound Envs with increased trimer stability through the introduction of key stabilization mutations. We derived a stabilized HIV-1 trimer, ConSOSL.UFO.750, which displays a dramatic reduction in nNAb binding while maintaining high quaternary and MPER-specific bNAb binding. Its soluble counterpart, ConSOSL.UFO.664, displays similar antigenicity, and its native-like Env structure is confirmed by negative stain-EM and glycosylation profiling of the soluble ConSOSL.UFO.664 trimer. A rabbit immunization study demonstrated that the ConSOSL.UFO.664 can induce autologous tier 2 neutralization. We have successfully designed a stabilized native-like Env trimer amenable to nucleic acid or viral vector-based vaccination strategies.