HIV broadly neutralizing antibody precursors to the Apex epitope induced in nonhuman primates
M. Krystal, Henry J. Sutton, Payal Pratap, Jon M. Steichen, Diane G. Carnathan, James C. Quinn, Oleksandr Kalyuzhniy, Alessia Liguori, Sashank Agrawal, Sabyasachi Baboo, Patrick Madden, Christopher A. Cottrell, Jordan R. Willis, Jeong Hyun Lee, Elise Landais, Xiaozhen Hu, Parham Ramezani-Rad, Gabriel Ozorowski, Vanessa Lewis, Jolene K. Diedrich, Xiaoya Zhou, Tasha K. Altheide, Nicole Phelps, Erik Georgeson, Nushin Alavi, Danny Lu, Saman Eskandarzadeh, Michael Kubitz, Yumiko Adachi, Tina-Marie Mullen, Murillo Silva, Mariane B. Melo, Sunny Himansu, Darrell J. Irvine, Dennis R. Burton, John R. Yates, James C. Paulson, Devin Sok, Ian A. Wilson, Guido Silvestri, Andrew B. Ward, Shane Crotty, William R. Schief
Abstract
An effective prophylactic HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). bnAbs to the Apex region of the HIV envelope glycoprotein (Env) are promising targets for vaccination because of their relatively low somatic hypermutation compared with other bnAbs. Most Apex bnAbs engage Env using an exceptionally long heavy-chain complementarity-determining region 3 (HCDR3) containing specific binding motifs, which reduces bnAb precursor frequency and makes priming of rare bnAb precursors a likely limiting step in the path to Apex bnAb induction. We found that adjuvanted protein or mRNA lipid nanoparticle (LNP) immunization of rhesus macaques with ApexGT6, an Env trimer engineered to bind Apex bnAb precursors, consistently induced Apex bnAb-related precursors with long HCDR3s bearing bnAb-like sequence motifs. Cryo-electron microscopy revealed that elicited Apex bnAb-related HCDR3s had structures combining elements of several prototype Apex bnAbs. These results achieve a critical HIV vaccine development milestone in outbred primates.