Abstract
Efforts to elicit broadly neutralizing antibodies (bNAbs) against HIV-1 require understanding germline bNAb recognition of HIV-1 envelope glycoprotein (Env). The VRC01-class bNAb family derived from the VH1-2*02 germline allele arose in multiple HIV-1-infected donors, yet targets the CD4-binding site on Env with common interactions. Modified forms of the 426c Env that activate germline-reverted B cell receptors are candidate immunogens for eliciting VRC01-class bNAbs. We present structures of germline-reverted VRC01-class bNAbs alone and complexed with 426c-based gp120 immunogens. Germline bNAb-426c gp120 complexes showed preservation of VRC01-class signature residues and gp120 contacts, but detectably different binding modes compared to mature bNAb-gp120 complexes. Unlike typical antibody-antigen interactions, VRC01-class germline antibodies exhibited preformed antigen-binding conformations for recognizing immunogens. Affinity maturation introduced substitutions increasing induced-fit recognition and electropositivity, potentially to accommodate negatively-charged complex-type N-glycans on gp120. These results provide general principles relevant to the unusual evolution of VRC01-class bNAbs and guidelines for structure-based immunogen design.
Highlights
The human immunodeficiency virus-1 (HIV-1) envelope (Env) spike, a trimer of gp120-gp41 heterodimers, is the only target of neutralizing antibodies (Abs)
We investigated VRC01-class germline recognition of envelope glycoprotein (Env) by solving a crystal structure of the clade A/E 93TH057 gp120 core bound to a half germline, half mature chimeric VRC01-class Ab (NIH45-46CHIM) in which the inferred germline heavy chain (HC) was paired with the mature LC to permit binding to an unmodified gp120 (Scharf et al, 2013)
The antigen-binding Fabs of two VRC01-class Abs isolated from different patients, NIH45-46 and 3BNC60 (Scheid et al, 2011), were generated in their inferred germline forms (NIH45-46GL and 3BNC60GL) using sequences described in previous studies (Scharf et al, 2013; Hoot et al, 2013; McGuire et al, 2013; Dosenovic et al, 2015)
Summary
The HIV-1 envelope (Env) spike, a trimer of gp120-gp heterodimers, is the only target of neutralizing antibodies (Abs). Potent bNAbs against the conserved CD4-binding site (CD4bs) on gp120 that were derived from the VH1-2*02 variable heavy chain (HC) gene have been isolated from at least nine HIV-1–infected individuals (Scheid et al, 2011; Wu et al, 2010; Zhou et al, 2013; 2015; Wu et al, 2011; Georgiev et al, 2013). These bNAbs exhibit unusually high levels of somatic hypermutation, with changes in both complementarity determining regions (CDRs) and framework regions (FWRs) (Klein et al, 2013).
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