title: Immunodominance of Antibody Recognition of the HIV Envelope V2 Region in Ig-Humanized Mice.
abstract: In the RV144 gp120 HIV vaccine trial, decreased transmission risk was correlated with Abs that reacted with a linear epitope at a lysine residue at position 169 (K169) in the HIV-1 envelope (Env) V2 region. The K169 V2 response was restricted to Abs bearing Vλ rearrangements that expressed aspartic acid/glutamic acid in CDR L2. The AE.A244 gp120 in AIDSVAX B/E also bound to the unmutated ancestor of a V2-glycan broadly neutralizing Ab, but this Ab type was not induced in the RV144 trial. In this study, we sought to determine whether immunodominance of the V2 linear epitope could be overcome in the absence of human Vλ rearrangements. We immunized IgH- and Igκ-humanized mice with the AE.A244 gp120 Env. In these mice, the V2 Ab response was focused on a linear epitope that did not include K169. V2 Abs were isolated that used the same human VH gene segment as an RV144 V2 Ab but paired with a mouse λ L chain. Structural characterization of one of these V2 Abs revealed how the linear V2 epitope could be engaged, despite the lack of aspartic acid/glutamic acid encoded in the mouse repertoire. Thus, despite the absence of the human Vλ locus in these humanized mice, the dominance of Vλ pairing with human VH for HIV-1 Env V2 recognition resulted in human VH pairing with mouse λ L chains instead of allowing otherwise subdominant V2-glycan broadly neutralizing Abs to develop.
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710; kevin.wiehe@dm.duke.edu barton.haynes@dm.duke.edu.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Kevin
authors.identifier: 0000-0001-9933-9618
authors.initials: K
authors.lastname: Wiehe
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Nathan I
authors.identifier: 0000-0002-0025-2377
authors.initials: NI
authors.lastname: Nicely
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Bradley
authors.initials: B
authors.lastname: Lockwood
authors.affiliation: Department of Immunology, Duke University, Durham, NC 27710.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kuraoka
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Kara
authors.initials: K
authors.lastname: Anasti
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Arora
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Cindy M
authors.identifier: 0000-0002-6903-2831
authors.initials: CM
authors.lastname: Bowman
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Christina
authors.identifier: 0000-0002-1429-5212
authors.initials: C
authors.lastname: Stolarchuk
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Robert
authors.initials: R
authors.lastname: Parks
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Krissey E
authors.initials: KE
authors.lastname: Lloyd
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Shi-Mao
authors.initials: SM
authors.lastname: Xia
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Ryan
authors.identifier: 0000-0001-6071-1574
authors.initials: R
authors.lastname: Duffy
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Shen
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Christos A
authors.initials: CA
authors.lastname: Kyratsous
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Macdonald
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Scearce
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.|Department of Immunology, Duke University, Durham, NC 27710.|Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710.
authors.forename: M Anthony
authors.identifier: 0000-0002-3890-5855
authors.initials: MA
authors.lastname: Moody
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.|Department of Pathology, Duke University School of Medicine, Durham, NC 27710; and.
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.|Department of Pathology, Duke University School of Medicine, Durham, NC 27710; and.
authors.forename: Laurent
authors.identifier: 0000-0001-7497-6645
authors.initials: L
authors.lastname: Verkoczy
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.|Department of Surgery, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Georgia D
authors.identifier: 0000-0001-8076-1931
authors.initials: GD
authors.lastname: Tomaras
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.|Department of Immunology, Duke University, Durham, NC 27710.
authors.forename: Garnett
authors.initials: G
authors.lastname: Kelsoe
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710.|Department of Immunology, Duke University, Durham, NC 27710.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D020816:Amino Acid Motifs; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000939:Epitopes; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000276:immunology; D007146:Immunoglobulin lambda-Chains / Q000276:immunology; D051379:Mice
chemical_list: D016915:AIDS Vaccines; C574872:AIDSVAX B-E; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007143:Immunoglobulin Heavy Chains; D007146:Immunoglobulin lambda-Chains