title: Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies.
abstract: A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb. Two autologous neutralizing antibody lineages selected for virus escape mutations and consequently allowed initiation and affinity maturation of a V3-glycan bnAb lineage. The nucleotide substitution required to initiate the bnAb lineage occurred at a low-probability site for activation-induced cytidine deaminase activity. Cooperation of B cell lineages and an improbable mutation critical for bnAb activity defined the necessary events leading to breadth in this V3-glycan bnAb lineage. These findings may, in part, explain why initiation of V3-glycan bnAbs is rare, and suggest an immunization strategy for inducing similar V3-glycan bnAbs.
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA. mattia.bonsignori@dm.duke.edu btk@lanl.gov barton.haynes@dm.duke.edu.|Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Mattia
authors.identifier: 0000-0003-2973-2101
authors.initials: M
authors.lastname: Bonsignori
authors.affiliation: Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Edward F
authors.identifier: 0000-0003-2330-8430
authors.initials: EF
authors.lastname: Kreider
authors.affiliation: Laboratory of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniela
authors.identifier: 0000-0002-1706-9288
authors.initials: D
authors.lastname: Fera
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.|Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: R Ryan
authors.identifier: 0000-0003-1253-2250
authors.initials: RR
authors.lastname: Meyerhoff
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.|Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Todd
authors.identifier: 0000-0002-8770-040X
authors.initials: T
authors.lastname: Bradley
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.|Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Kevin
authors.identifier: 0000-0001-9933-9618
authors.initials: K
authors.lastname: Wiehe
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.|Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: S Munir
authors.identifier: 0000-0003-0941-0703
authors.initials: SM
authors.lastname: Alam
authors.affiliation: Department of Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Baptiste
authors.identifier: 0000-0002-8828-8963
authors.initials: B
authors.lastname: Aussedat
authors.affiliation: Department of Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: William E
authors.identifier: 0000-0002-7961-1175
authors.initials: WE
authors.lastname: Walkowicz
authors.affiliation: Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Kwan-Ki
authors.identifier: 0000-0002-3903-6997
authors.initials: KK
authors.lastname: Hwang
authors.affiliation: Duke Human Vaccine Institute, Durham, NC 27710, USA.|Department of Surgery, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Kevin O
authors.initials: KO
authors.lastname: Saunders
authors.affiliation: Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Ruijun
authors.identifier: 0000-0002-2342-8232
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Morgan A
authors.initials: MA
authors.lastname: Gladden
authors.affiliation: Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Anthony
authors.identifier: 0000-0001-9428-3555
authors.initials: A
authors.lastname: Monroe
authors.affiliation: Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Shi-Mao
authors.initials: SM
authors.lastname: Xia
authors.affiliation: Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Cooper
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mark K
authors.identifier: 0000-0001-7540-9263
authors.initials: MK
authors.lastname: Louder
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Krisha
authors.initials: K
authors.lastname: McKee
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Bailer
authors.affiliation: Laboratory of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Brendan W
authors.initials: BW
authors.lastname: Pier
authors.affiliation: Laboratory of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Jette
authors.affiliation: Duke Human Vaccine Institute, Durham, NC 27710, USA.|Department of Immunology, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Garnett
authors.identifier: 0000-0002-8770-040X
authors.initials: G
authors.lastname: Kelsoe
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.|Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Wilton B
authors.identifier: 0000-0002-2970-7259
authors.initials: WB
authors.lastname: Williams
authors.affiliation: National Institute for Communicable Diseases, Johannesburg 2131, South Africa.
authors.forename: Lynn
authors.identifier: 0000-0003-3961-7828
authors.initials: L
authors.lastname: Morris
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kappes
authors.affiliation: Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
authors.forename: Kshitij
authors.initials: K
authors.lastname: Wagh
authors.affiliation: University of North Carolina Project, Kamuzu Central Hospital, Lilongwe, Malawi.
authors.forename: Gift
authors.initials: G
authors.lastname: Kamanga
authors.affiliation: Departments of Medicine, Epidemiology, and Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Myron S
authors.identifier: 0000-0001-5917-9664
authors.initials: MS
authors.lastname: Cohen
authors.affiliation: Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
authors.forename: Peter T
authors.identifier: 0000-0002-2920-4897
authors.initials: PT
authors.lastname: Hraber
authors.affiliation: Duke Human Vaccine Institute, Durham, NC 27710, USA.|Department of Surgery, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Ashley
authors.identifier: 0000-0001-7686-0902
authors.initials: A
authors.lastname: Trama
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.|Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Department of Microbiology and Department of Mathematics and Statistics, Boston University, Boston, MA 02215, USA.
authors.forename: Thomas B
authors.identifier: 0000-0002-1383-6865
authors.initials: TB
authors.lastname: Kepler
authors.affiliation: Duke Human Vaccine Institute, Durham, NC 27710, USA.|Department of Immunology, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.|Department of Pediatrics, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: M Anthony
authors.identifier: 0000-0002-3890-5855
authors.initials: MA
authors.lastname: Moody
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.|Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Feng
authors.identifier: 0000-0001-8903-0203
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Danishefsky
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: John R
authors.identifier: 0000-0002-5293-4695
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: Laboratory of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harrison
authors.affiliation: Los Alamos National Laboratory, Los Alamos, NM 87545, USA. mattia.bonsignori@dm.duke.edu btk@lanl.gov barton.haynes@dm.duke.edu.
authors.forename: Bette T
authors.identifier: 0000-0002-2026-5757
authors.initials: BT
authors.lastname: Korber
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA. mattia.bonsignori@dm.duke.edu btk@lanl.gov barton.haynes@dm.duke.edu.|Duke Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Barton F
authors.identifier: 0000-0002-2847-1854
authors.initials: BF
authors.lastname: Haynes
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D009500:Neutralization Tests; D010802:Phylogeny; D011134:Polysaccharides / Q000378:metabolism*; D011485:Protein Binding; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D011134:Polysaccharides; D054299:env Gene Products, Human Immunodeficiency Virus