title: Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site.
abstract: Eliciting broad tier 2 neutralizing antibodies (nAbs) is a major goal of HIV-1 vaccine research. Here we investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit nAbs. Unusually potent nAb titers developed in 2 of 8 rabbits immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and in 1 of 20 rabbits immunized with DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. Specifically, trimer VLP sera took advantage of the unusual absence of a glycan at residue 197 (present in 98.7% of Envs). Intriguingly, removing the N197 glycan (with no loss of tier 2 phenotype) rendered 50% or 16.7% (n = 18) of clade B tier 2 isolates sensitive to the two trimer VLP sera, showing broad neutralization via the surface masked by the N197 glycan. Neutralizing sera targeted epitopes that overlap with the CD4 binding site, consistent with the role of the N197 glycan in a putative "glycan fence" that limits access to this region. A bioinformatics analysis suggested shared features of one of the trimer VLP sera and monoclonal antibody PG9, consistent with its trimer-dependency. The neutralizing DNA trimer serum took advantage of the absence of a glycan at residue 230, also proximal to the CD4 binding site and suggesting an epitope similar to that of monoclonal antibody 8ANC195, albeit lacking tier 2 breadth. Taken together, our data show for the first time that strain-specific holes in the glycan fence can allow the development of tier 2 neutralizing antibodies to native spikes. Moreover, cross-neutralization can occur in the absence of protecting glycan. Overall, our observations provide new insights that may inform the future development of a neutralizing antibody vaccine.
authors.affiliation: San Diego Biomedical Research Institute, San Diego, California, United States of America.
authors.forename: Ema T
authors.initials: ET
authors.lastname: Crooks
authors.affiliation: San Diego Biomedical Research Institute, San Diego, California, United States of America.
authors.forename: Tommy
authors.initials: T
authors.lastname: Tong
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, California, United States of America.
authors.forename: Bimal
authors.initials: B
authors.lastname: Chakrabarti
authors.affiliation: Altravax, Inc., Sunnyvale, California, United States of America.
authors.forename: Kristin
authors.initials: K
authors.lastname: Narayan
authors.affiliation: Vaccine Research Center, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Ivelin S
authors.initials: IS
authors.lastname: Georgiev
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, California, United States of America; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Sergey
authors.initials: S
authors.lastname: Menis
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Huang
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, California, United States of America; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kulp
authors.affiliation: San Diego Biomedical Research Institute, San Diego, California, United States of America.
authors.forename: Keiko
authors.initials: K
authors.lastname: Osawa
authors.affiliation: Altravax, Inc., Sunnyvale, California, United States of America.
authors.forename: Janelle
authors.initials: J
authors.lastname: Muranaka
authors.affiliation: Vaccine Research Center, National Institutes of Health (NIH), Bethesda, Maryland, United States of America; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, The John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Stewart-Jones
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Joanne
authors.initials: J
authors.lastname: Destefano
authors.affiliation: Vaccine Research Center, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Sijy
authors.initials: S
authors.lastname: O'Dell
authors.affiliation: Department of Surgery, Duke University, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Celia
authors.initials: C
authors.lastname: LaBranche
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, United States of America.
authors.forename: James E
authors.initials: JE
authors.lastname: Robinson
authors.affiliation: Department of Surgery, Duke University, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Vaccine Research Center, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Krisha
authors.initials: K
authors.lastname: McKee
authors.affiliation: Altravax, Inc., Sunnyvale, California, United States of America.
authors.forename: Sean X
authors.initials: SX
authors.lastname: Du
authors.affiliation: Vaccine Research Center, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Doria-Rose
authors.affiliation: Vaccine Research Center, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Vaccine Research Center, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, California, United States of America; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America; Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: William R
authors.initials: WR
authors.lastname: Schief
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, California, United States of America; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wyatt
authors.affiliation: Altravax, Inc., Sunnyvale, California, United States of America.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Whalen
authors.affiliation: San Diego Biomedical Research Institute, San Diego, California, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Binley
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001665:Binding Sites; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005260:Female; D006168:Guinea Pigs; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007114:Immunization; D011134:Polysaccharides / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D011487:Protein Conformation; D011817:Rabbits
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D011134:Polysaccharides