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. 2018 Nov 5;14(11):e1007431.
doi: 10.1371/journal.ppat.1007431. eCollection 2018 Nov.

HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies

Celia C LaBranche  1 , Andrew T McGuire  2 , Matthew D Gray  2 , Shay Behrens  1 , Peter D Kwong, Xuejun Chen  3 , Tongqing Zhou  3 , Quentin J Sattentau  4 , James Peacock  5 , Amanda Eaton  1 , Kelli Greene  1 , Hongmei Gao  1 , Haili Tang  1 , Lautaro G Perez  1 , Xuejun Chen, Kevin O Saunders  1 , Peter D Kwong  3 , John R Mascola  3 , Barton F Haynes  5 , Leonidas Stamatatos  2   6 , David C Montefiori  1
Affiliations

HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies

Celia C LaBranche et al. PLoS Pathog. .

Erratum in

Abstract

Broadly neutralizing antibody (bnAb) induction is a high priority for effective HIV-1 vaccination. VRC01-class bnAbs that target the CD4 binding site (CD4bs) of trimeric HIV-1 envelope (Env) glycoprotein spikes are particularly attractive to elicit because of their extraordinary breadth and potency of neutralization in vitro and their ability to protect against infection in animal models. Glycans bordering the CD4bs impede the binding of germline-reverted forms of VRC01-class bnAbs and therefore constitute a barrier to early events in initiating the correct antibody lineages. Deleting a subset of these glycans permits Env antigen binding but not virus neutralization, suggesting that additional barriers impede germline-reverted VRC01-class antibody binding to functional Env trimers. We investigated the requirements for functional Env trimer engagement of VRC01-class naïve B cell receptors by using virus neutralization and germline-reverted antibodies as surrogates for the interaction. Targeted deletion of a subset of N-glycans bordering the CD4bs, combined with Man5 enrichment of remaining N-linked glycans that are otherwise processed into larger complex-type glycans, rendered HIV-1 426c Env-pseudotyped virus (subtype C, transmitted/founder) highly susceptible to neutralization by near germline forms of VRC01-class bnAbs. Neither glycan modification alone rendered the virus susceptible to neutralization. The potency of neutralization in some cases rivaled the potency of mature VRC01 against wildtype viruses. Neutralization by the germline-reverted antibodies was abrogated by the known VRC01 resistance mutation, D279K. These findings improve our understanding of the restrictions imposed by glycans in eliciting VRC01-class bnAbs and enable a neutralization-based strategy to monitor vaccine-elicited early precursors of this class of bnAbs.

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Conflict of interest statement

The authors have declared that no competing interests exist

Figures

Fig 1
Fig 1. Complementarity of targeted glycan-deletion and Man5-enrichement for neutralization by germline-reverted VRC01.
Parental and glycan deletion mutants of 426c were produced as Env-pseudotyped viruses in 293T and 293S GnT1- cells and assayed for neutralization by mature and germline-reverted VRC01 in TZM-bl cells. The 426c glycan deletion mutants were SM (N276D), DM (N460D.N463D), TM1 (N276D.N460D.N463D) and TM4 (S278R.G471S.N460D.N463D).
Fig 2
Fig 2. Detection and epitope mapping of neutralization by germline-reverted forms of VRC01-class bnAbs.
(A) Germline reverted forms of the indicated bnAbs were assayed in TZM-bl cells against Env-pseudotyped viruses 426c, 426c.SM (N276D), 426c.DM (N260D.N463D), 426c.TM1 (N276D.N460D.N463D) and 426c.TM4 (S278R.G471S.N460D.N463D) produced in 293S GnT1- cells. (B) Germline-reverted forms of VRC01, VRC07 and VRC20 were assayed in TZM-bl cells against 426c.TM1 and 426c.TM1.D279K produced in 293S GnT1- cells.
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