Kavli Affiliate: Robert Edwards
| Authors: Frederic 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, Younghoon Park, Rachel Baum, Andrew Connell, Hui Li, Elena E Giorgi, Ge S Song, Shilei Ding, Andres Finzi, Amanda Newman, Giovanna E Hernandez, Emily Machiele, Derek W Cain, Katayoun Mansouri, Mark G Lewis, David C Montefiori, Kevin J Wiehe, S. Munir Alam, I-Ting Teng, Peter D Kwong, Raiees Andrabi, Laurent Verkoczy, Dennis R Burton, Bette T Korber, Kevin O Saunders, Barton F Haynes, Robert J Edwards, George M Shaw and Beatrice H Hahn
| Summary:
Abstract HIV-1 and its SIV precursors share a broadly neutralizing antibody (bNAb) epitope in variable loop 2 (V2) at the envelope glycoprotein (Env) trimer apex. Here, we tested the immunogenicity of germline-targeting versions of a chimpanzee SIV (SIVcpz) Env in human V2-apex bNAb heavy-chain precursor-expressing knock-in mice and as chimeric simian-chimpanzee immunodeficiency viruses (SCIVs) in rhesus macaques (RMs). Trimer immunization of knock-in mice induced V2-directed NAbs, indicating activation of V2-apex bNAb precursor-expressing mouse B cells. SCIV infection of RMs elicited high-titer viremia, potent autologous tier 2 neutralizing antibodies, and rapid sequence escape in the canonical V2-apex epitope. Six of seven animals also developed low-titer heterologous plasma breadth that mapped to the V2-apex. Antibody cloning from two of these identified multiple expanded lineages with long heavy chain third complementarity determining regions that cross-neutralized as many as 7 of 19 primary HIV-1 strains, but with low potency. Negative stain electron microscopy (NSEM) of members of the two most cross-reactive lineages confirmed V2 targeting but identified an angle of approach distinct from prototypical V2-apex bNAbs, with antibody binding either requiring or inducing an occluded-open trimer. Probing with conformation-sensitive, non-neutralizing antibodies revealed that SCIV-expressed Envs as well as some primary HIV-1 Envs adopted a more open conformation, thereby exposing a conserved V2 epitope that is occluded in closed SIVcpz and HIV-1 Env trimers. These results expand the spectrum of V2-apex targeted antibodies that can contribute to neutralization breadth and identify novel SIV Env platforms for further development as germline-targeting and immunofocusing immunogens. One sentence summary A cryptic V2 epitope in occluded-open HIV and SIV Env trimers is the target of a new class of V2-directed cross-neutralizing antibodies. Competing Interest Statement The authors have declared no competing interest.