Abstract
SummaryElicitation of VRC01-class broadly neutralizing antibodies (bnAbs) is an appealing approach for a preventative HIV-1 vaccine. Despite extensive investigations, strategies to induce VRC01-class bnAbs and overcome the barrier posed by the envelope N276 glycan have not been successful. Here, we inferred a high-probability unmutated common ancestor (UCA) of the VRC01 lineage and reconstructed the stages of lineage maturation. Env immunogens designed on reverted VRC01-class bnAbs bound to VRC01 UCA with affinity sufficient to activate naive B cells. Early mutations defined maturation pathways toward limited or broad neutralization, suggesting that focusing the immune response is likely required to steer B cell maturation toward the development of neutralization breadth. Finally, VRC01 lineage bnAbs with long CDR H3s overcame the HIV-1 N276 glycan barrier without shortening their CDR L1, revealing a solution for broad neutralization in which the heavy chain, not CDR L1, is the determinant to accommodate the N276 glycan.
Highlights
The first step to initiate broadly neutralizing antibody (bnAb) lineage maturation is to engage naive B cells expressing the unmutated IgH and IgL precursor, referred to as the ‘‘unmutated common ancestor’’ (UCA) of the lineage (Haynes et al, 2012; Kepler et al, 2014)
The importance of an accurate inference of the complementarity-determining region (CDR) H3 is underscored by recent findings indicating that, among VRC01-class bnAb precursors, the CDR H3 plays a more predominant role in HIV-1 gp120 envelope glycoprotein (Env) recognition than once thought (Yacoob et al, 2016)
Inference of the VRC01 UCA To infer the UCA of the VRC01 lineage, we used 45 naturally paired IgH+IgL VRC01 lineage monoclonal antibodies (mAbs) isolated from memory B cells of National Institutes of Health (NIH) donor 45, from whom the VRC01 bnAb was isolated (Wu et al, 2010)
Summary
The first step to initiate bnAb lineage maturation is to engage naive B cells expressing the unmutated IgH and IgL precursor, referred to as the ‘‘unmutated common ancestor’’ (UCA) of the lineage (Haynes et al, 2012; Kepler et al, 2014). The importance of an accurate inference of the CDR H3 is underscored by recent findings indicating that, among VRC01-class bnAb precursors, the CDR H3 plays a more predominant role in HIV-1 gp120 envelope glycoprotein (Env) recognition than once thought (Yacoob et al, 2016). This approach has yielded the design of multiple immunogens that bind to GL VRC01-class monoclonal antibodies (mAbs). HIV-1 426c Env-derived core proteins, in which the variable loops 1, 2, and 3 were deleted (Dosenovic et al, 2015; McGuire et al, 2016), as well as a stabilized BG505 Env-derived SOSIP v4.1-GT1 trimer (referred to as ‘‘GT1 trimer’’ in this paper) (Medina-Ramırez et al, 2017) activate germline-reverted VRC01 B cells in knock-in mic
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