Author:
Bibollet-Ruche Frederic,Russell Ronnie M.,Ding Wenge,Liu Weimin,Li Yingying,Wagh Kshitij,Wrapp Daniel,Habib Rumi,Skelly Ashwin N.,Roark Ryan S.,Sherrill-Mix Scott,Wang Shuyi,Rando Juliette,Lindemuth Emily,Cruickshank Kendra,Park Younghoon,Baum Rachel,Connell Andrew Jesse,Li Hui,Giorgi Elena E.,Song Ge S.,Ding Shilei,Finzi Andrés,Newman Amanda,Hernandez Giovanna E.,Machiele Emily,Cain Derek W.,Mansouri Katayoun,Lewis Mark G.,Montefiori David C.,Wiehe Kevin J.,Alam S. Munir,Teng I-Ting,Kwong Peter D.,Andrabi Raiees,Verkoczy Laurent,Burton Dennis R.,Korber Bette T.,Saunders Kevin O.,Haynes Barton F.,Edwards Robert J.,Shaw George M.,Hahn Beatrice H.
Abstract
AbstractHIV-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 summaryA cryptic V2 epitope in occluded-open HIV and SIV Env trimers is the target of a new class of V2-directed cross-neutralizing antibodies.
Publisher
Cold Spring Harbor Laboratory