Immunodominance of antibody recognition of the HIV envelope second variable region in immunoglobulin humanized mice

• Published in: The Journal of immunology (1950) Vol. 198; no. 3; pp. 1047 - 1055
• Main Authors: Wiehe, Kevin, Nicely, Nathan I., Lockwood, Bradley, Kuraoka, Masayuki, Anasti, Kara, Arora, Sabrina, Bowman, Cindy M., Stolarchuk, Christina, Parks, Robert, Lloyd, Krissey E., Xia, Shi-Mao, Duffy, Ryan, Shen, Xiaoying, Kyratsous, Christos A., Macdonald, Lynn E., Murphy, Andrew J., Scearce, Richard M., Moody, M. Anthony, Alam, S. Munir, Verkoczy, Laurent, Tomaras, Georgia D., Kelsoe, Garnett, Haynes, Barton F.
• Format: Journal Article
• Language: English
• Published: 23-12-2016
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601640

In the RV144 gp120 HIV vaccine trial, decreased transmission risk was correlated with antibodies that reacted with a linear epitope at a lysine at position 169 (K169) in the HIV-1 envelope (Env) second variable (V2) loop. The K169 V2 response was restricted to antibodies bearing Vλ rearrangements that expressed aspartic acid/glutamic acid (ED motif) in CDR L2. The AE.A244 gp120 in AIDSVAX B/E also bound to the unmutated ancestor of a V2-glycan broadly neutralizing antibody (bnAb), but this antibody type was not induced in the RV144 trial. Here we sought to determine if 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 antibody response was focused on a linear epitope that did not include K169. V2 antibodies were isolated that utilized the same human VH gene segment as an RV144 V2 antibody, but paired with a mouse lambda light chain. Structural characterization of one of these V2 antibodies revealed how the linear V2 epitope could be engaged despite the lack of an ED motif encoded in the mouse repertoire. Thus, in spite of 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 lambda light chains instead of allowing otherwise subdominant V2-glycan bnAbs to develop.