Bai, H.; Lewitus, E.; Li, Y.; Dussupt, V.; Slike, B.; Mendez-Rivera, L.; Schmid, A.; Wieczorek, L.; Polonis, V.; Krebs, S. J.; Ake, J. A.; Vasan, S.; Joyce, M. G.; Townsley, S.; Rolland, M.

An effective HIV-1 vaccine must elicit broadly neutralizing antibodies (bnAbs) against the highly diverse Envelope glycoproteins (Env) present globally. Since Env with the longest hypervariable (HV) loops were more resistant to the cognate bnAbs than Env with shorter HV loops, we redesigned hypervariable loops for updated HIV-1 Env consensus sequences of subtypes B and C and circulating recombinant form AE (CRF01_AE). We reduced the length of V1HV, V2H, and V5HV while maintaining the integrity of the Env structure and glycan shield, and we modified V4HV to account for its diverse structural context. Redesiged HV loops consisted mainly of glycine and serine to limit strain-specific targeting. Redesigned consensus Env of subtype B or CRF01_AE demonstrated increased magnitude of binding responses to pooled plasma samples and representative bnAbs. Together with other antigen optimization techniques, consensus Env with redesigned hypervariable loops can improve future HIV-1 vaccine antigens to elicit bnAbs.