Rapid elicitation of neutralizing Asn332-glycan-independent antibodies to the V3-glycan epitope of HIV-1 Env in nonhuman primates
Ignacio Relaño-Rodríguez, Jianqiu Du, Zi Jie Lin, Margaret Kerwin, Marta Tarquis-Medina, Eduardo Urbano, Jiayan Cui, Meagan Watkins, Christy L. Lavine, Peng Zhao, Rumi Habib, Colby J. Agostino, Sukanya Ghosh, Joyce Park, Caroline Boroughs, Agnes A. Walsh, Mariane B. Melo, N. Shukla, George M. Shaw, Beatrice H. Hahn, Darrell J. Irvine, Lance Wells, David B. Weiner, Michael S. Seaman, Daniel W. Kulp, Ronald S. Veazey, Jesper Pallesen, Amelia Escolano
Abstract
Sequential immunization is a promising approach to elicit broadly neutralizing antibodies (bNAbs) against the HIV-1 Envelope (Env). However, available protocols are inefficient and involve multiple immunizations over long periods of time. Here, we present WIN332, a new engineered Env immunogen that induces a new class of Asn332-glycan-independent antibodies to the conserved V3-glycan epitope of Env with low inhibitory activity indicative of a neutralization activity after a single bolus immunization in nonhuman primates. WIN332 binds to precursors of canonical human Asn332-glycan-dependent (type-I) V3-glycan bNAbs but also of a first-of-its-class Asn332-glycan-independent (type-II) V3-glycan bNAb. A single immunization elicits low inhibitory serum and monoclonal antibodies that are boosted and affinity matured with a heterologous immunogen. Electron microscopy polyclonal epitope mapping analysis of serum antibodies, antibody cloning and cryogenic electron microscopy analysis reveals that WIN332 elicits Asn332-glycan-independent antibodies with striking sequence and binding similarities with the most potent human type-I and type-II V3-glycan bNAbs. Thus, WIN332 is a promising vaccine candidate to streamline V3-glycan bNAb elicitation. WIN332 is an HIV-1 Env protein designed to elicit a new class of Asn332-glycan-independent antibodies (type II) to the V3-glycan site of Env. WIN332 immunization rapidly induces type-II V3-glycan antibodies with low inhibitory activity indicative of a neutralization activity in macaques.