5kg9 | pdb_00005kg9
Crystal structure of the gp120 v2 antibody RE505-22 Fab from IGH- and IGK-humanized mouse
Structural highlights
Publication Abstract from PubMedIn 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 Vlambda 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 Vlambda rearrangements. We immunized IgH- and Igkappa-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 lambda 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 Vlambda locus in these humanized mice, the dominance of Vlambda pairing with human VH for HIV-1 Env V2 recognition resulted in human VH pairing with mouse lambda L chains instead of allowing otherwise subdominant V2-glycan broadly neutralizing Abs to develop. Immunodominance of Antibody Recognition of the HIV Envelope V2 Region in Ig-Humanized Mice.,Wiehe K, Nicely NI, Lockwood B, Kuraoka M, Anasti K, Arora S, Bowman CM, Stolarchuk C, Parks R, Lloyd KE, Xia SM, Duffy R, Shen X, Kyratsous CA, Macdonald LE, Murphy AJ, Scearce RM, Moody MA, Alam SM, Verkoczy L, Tomaras GD, Kelsoe G, Haynes BF J Immunol. 2017 Feb 1;198(3):1047-1055. doi: 10.4049/jimmunol.1601640. Epub 2016 , Dec 23. PMID:28011932[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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