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2017 ; 214
(9
): 2573-2590
Nephropedia Template TP
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English Wikipedia
Design and crystal structure of a native-like HIV-1 envelope trimer that engages
multiple broadly neutralizing antibody precursors in vivo
#MMPMID28847869
Medina-Ramírez M
; Garces F
; Escolano A
; Skog P
; de Taeye SW
; Del Moral-Sanchez I
; McGuire AT
; Yasmeen A
; Behrens AJ
; Ozorowski G
; van den Kerkhof TLGM
; Freund NT
; Dosenovic P
; Hua Y
; Gitlin AD
; Cupo A
; van der Woude P
; Golabek M
; Sliepen K
; Blane T
; Kootstra N
; van Breemen MJ
; Pritchard LK
; Stanfield RL
; Crispin M
; Ward AB
; Stamatatos L
; Klasse PJ
; Moore JP
; Nemazee D
; Nussenzweig MC
; Wilson IA
; Sanders RW
J Exp Med
2017[Sep]; 214
(9
): 2573-2590
PMID28847869
show ga
Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope
glycoprotein immunogens would be a major advance toward an effective vaccine. A
critical step in this process is the activation of naive B cells expressing
germline (gl) antibody precursors that have the potential to evolve into bNAbs.
Here, we reengineered the BG505 SOSIP.664 glycoprotein to engage gl precursors of
bNAbs that target either the trimer apex or the CD4-binding site. The resulting
BG505 SOSIP.v4.1-GT1 trimer binds multiple bNAb gl precursors in vitro.
Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show
that this trimer activates B cells in vivo, resulting in the secretion of
specific antibodies into the sera. A crystal structure of the gl-targeting trimer
at 3.2-Ĺ resolution in complex with neutralizing antibodies 35O22 and 9H+109L
reveals a native-like conformation and the successful incorporation of design
features associated with binding of multiple gl-bNAb precursors.