A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies.

Autor: Bibollet-Ruche F; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Russell RM; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Ding W; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Liu W; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Li Y; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Wagh K; Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA., Wrapp D; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA., Habib R; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Skelly AN; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Roark RS; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Sherrill-Mix S; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Wang S; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Rando J; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Lindemuth E; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Cruickshank K; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Park Y; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Baum R; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Carey JW; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Connell AJ; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Li H; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Giorgi EE; Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA., Song GS; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA., Ding S; Centre de Recherche du CHUM, Montreal, Quebec, Canada.; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada., Finzi A; Centre de Recherche du CHUM, Montreal, Quebec, Canada.; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada., Newman A; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA., Hernandez GE; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA., Machiele E; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA., Cain DW; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA., Mansouri K; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA., Lewis MG; Bioqual, Inc., Rockville, Maryland, USA., Montefiori DC; Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA., Wiehe KJ; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA., Alam SM; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA., Teng IT; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Kwong PD; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Andrabi R; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA., Verkoczy L; San Diego Biomedical Research Institute, San Diego, California, USA., Burton DR; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA.; Ragon Institute of MGH, Harvard and MIT, Cambridge, Massachusetts, USA., Korber BT; Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA., Saunders KO; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA., Haynes BF; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA., Edwards RJ; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA., Shaw GM; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Hahn BH; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Jazyk: angličtina
Zdroj: MBio [mBio] 2023 Feb 28; Vol. 14 (1), pp. e0337022. Date of Electronic Publication: 2023 Jan 11.
DOI: 10.1128/mbio.03370-22
Abstrakt: 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.
Databáze: MEDLINE