Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires.
The design of immunogens that elicit broadly reactive neutralizing antibodies (bnAbs) has been a major obstacle to HIV-1 vaccine development. One approach to assess potential immunogens is to use mice expressing precursors of human bnAbs as vaccination models. The bnAbs of the VRC01-class derive from the IGHV1-2 immunoglobulin heavy chain and neutralize a wide spectrum of HIV-1 strains via targeting the CD4 binding site of the envelope glycoprotein gp120. We now describe a mouse vaccination model that allows a germline human IGHV1-2(∗)02 segment to undergo normal V(D)J recombination and, thereby, leads to the generation of peripheral B cells that express a highly diverse repertoire of VRC01-related receptors. When sequentially immunized with modified gp120 glycoproteins designed to engage VRC01 germline and intermediate antibodies, IGHV1-2(∗)02-rearranging mice, which also express a VRC01-antibody precursor light chain, can support the affinity maturation of VRC01 precursor antibodies into HIV-neutralizing antibody lineages.
Tian, M; Cheng, C; Chen, X; Duan, H; Cheng, H-L; Dao, M; Sheng, Z; Kimble, M; Wang, L; Lin, S; Schmidt, SD; Du, Z; Joyce, MG; Chen, Y; DeKosky, BJ; Chen, Y; Normandin, E; Cantor, E; Chen, RE; Doria-Rose, NA; Zhang, Y; Shi, W; Kong, W-P; Choe, M; Henry, AR; Laboune, F; Georgiev, IS; Huang, P-Y; Jain, S; McGuire, AT; Georgeson, E; Menis, S; Douek, DC; Schief, WR; Stamatatos, L; Kwong, PD; Shapiro, L; Haynes, BF; Mascola, JR; Alt, FW
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