A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies.
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| 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 germ line-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 animals 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, nonneutralizing antibodies revealed that SCIV-expressed, but not wild-type SIVcpz Envs, as well as a subset of primary HIV-1 Envs, preferentially adopted a more open trimeric state. These results reveal the existence of a cryptic V2 epitope that is exposed in occluded-open SIVcpz and HIV-1 Env trimers and elicits cross-neutralizing responses of limited breadth and potency. IMPORTANCE 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.
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| 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, John W Carey, Andrew Jesse Connell, Hui Li, Elena E Giorgi, Ge S Song, Shilei Ding, Andrés 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, Beatrice H Hahn |
| Journal | mBio (mBio) Vol. 14 Issue 1 Pg. e0337022 (02 28 2023) ISSN: 2150-7511 [Electronic] United States |
| PMID | 36629414 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Intramural) |
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