Previous studies have found that the CD4 binding site (CD4bs) of the HIV-1 envelope glycoprotein is susceptible to multiple lineages of broadly neutralising antibodies (bnAbs). One lineage, CH235 (VH1-46), contains mature members that neutralise 90% of circulating strains, do not possess long HCDR3 regions, and do not contain insertions and deletions that may be difficult to induce through vaccination. The authors used virus neutralisation to measure the interaction of the CH235 unmutated common ancestor (CH235 UCA) with functional Env trimers on infectious virions in order to guide immunogen design for this bnAb lineage. The authors identified two Env mutations, one in loop D (N279K) and another in V5 (G458Y), that act synergistically to render autologous CH505 transmitted/founder virus susceptible to neutralisation by CH235 UCA. Additional synergy was provided by Man5-enriched N-glycans. CH235 UCAwas found to bind with nanomolar affinity to corresponding soluble native-like Env trimers as candidate immunogens. Cryo-EM structural analysis of CH235 UCA bound to Man5-enriched CH505.N279K.G458Y.SOSIP.664 found that there are interactions of the antibody light chain complementarity determining region 3 (CDR L3) with the engineered Env loops D and V5. Therefore virus neutralisation directly informs vaccine design, suggesting that a germline targeting and reverse engineering strategy can initiate and mature the CH235 bnAb lineage.
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