A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies
Frédéric Bibollet‐Ruche, Ronnie M. Russell, Wenge Ding, Weimin Liu, Yingying Li, Kshitij Wagh, Daniel Wrapp, Rumi Habib, Ashwin N. Skelly, Ryan S. Roark, Scott Sherrill-Mix, Shuyi Wang, Juliette Rando, Emily Lindemuth, Kendra Cruickshank, Young-Hoon Park, Rachel Baum, John W. Carey, Andrew Connell, Hui Li, Elena E. Giorgi, Ge Song, Shilei Ding, Andrés Finzi, Amanda Newman, Giovanna E. Hernandez, Emily Machiele, Derek W. Cain, Katayoun Mansouri, Mark G. Lewis, David C. Montefiori, Kevin Wiehe, S. Munir Alam, I‐Ting Teng, Peter D. Kwong, Raiees Andrabi, Laurent Verkoczy, Dennis R. Burton, Bette Korber, Kevin O. Saunders, Barton F. Haynes, Robert J. Edwards, George M. Shaw, Beatrice H. Hahn
Abstract
An effective HIV-1 vaccination strategy will need to stimulate rare precursor B cells of multiple bNAb lineages and affinity mature them along desired pathways. Here, we searched for V2-apex germ line-targeting Envs among a large set of diverse primate lentiviruses and identified minimally modified versions of one chimpanzee SIV Env that bound several human V2-apex bNAb precursors and stimulated one of these in a V2-apex bNAb precursor-expressing knock-in mouse. We also generated chimeric simian-chimpanzee immunodeficiency viruses and showed that they elicit low-titer V2-directed heterologous plasma breadth in six of seven infected rhesus macaques. Characterization of this antibody response identified a new class of weakly cross-reactive neutralizing antibodies that target the V2-apex, but only in occluded-open Env trimers. The existence of this cryptic epitope, which in some Env backgrounds is immunodominant, needs to be considered in immunogen design.