VRC34-Antibody Lineage Development Reveals How a Required Rare Mutation Shapes the Maturation of a Broad HIV-Neutralizing Lineage

Abstract

Highlights d Maturation of VRC34 lineage bifurcates early along VRC34.01 and VRC34.05 branches d VRC34.01 branch requires the rare mutation Y33P HC to achieve broad neutralization d VRC34.05 branch utilizes Y33 to bind FP and does not achieve broad neutralization d An early rare mutation shapes VRC34-lineage development and neutralization breadth

Rapid selection of HIV envelopes that bind to neutralizing antibody B cell lineage members with functional improbable mutations

“…Of the 12 acquired mutations present in the minimized DH270.6, 10 were improbable based on computational predictions that estimate the propensity of AID to mutate the antibody gene regions where they are located (Wiehe et al, 2018). HIV bnAbs are enriched for improbable mutations and such mutations have been shown to have important functional roles across different antibodies (Bonsignori et al, 2016; Shen et al, 2020). Forty-three percent of the acquired mutations maintained in the minVRC01 antibody and 27% of those in minBG18 are improbable (Wiehe et al, 2018).…”

“…Recently, it was shown that HIV bnAbs are enriched for improbable mutations acquired during affinity maturation (Shen et al, 2020; Wiehe et al, 2018). These amino acid changes are expected to occur with low frequency naturally, either because they occur in gene regions that are not typically targeted by the Activation-Induced Cytidine Deaminase (AID) or due to the number of nucleotide changes required to transform a respective UCA amino acid into the mature one (Hwang et al, 2017; Yaari et al, 2013).…”

“…For example, in the evolution of the DH270.6 bnAb, the acquisition of an improbable glycine to arginine mutation at position 57 in the heavy chain initiates the development of heterologous neutralization breadth (Bonsignori et al, 2017a). Similarly, in the VRC34 lineage the only branch that gives rise to bnAbs acquired a rare tyrosine to proline mutation that is essential for broad neutralizing activity (Shen et al, 2020). Since improbable functional mutations represent rare events that restrict bnAb development, antibodies with such sequence changes will likely need to be explicitly selected by candidate immunogens in vaccinations.…”

“…These amino acid changes are expected to occur with low frequency naturally, either because they occur in gene regions that are not typically targeted by the Activation-Induced Cytidine Deaminase (AID) or due to the number of nucleotide changes required to transform a respective UCA amino acid into the mature one (Hwang et al, 2017; Yaari et al, 2013). Notably, improbable mutations typically play a critical role in HIV bnAb function and represent developmental barriers that need to be overcome for the development of neutralization breadth (Bonsignori et al, 2017a; Shen et al, 2020). For example, in the evolution of the DH270.6 bnAb, the acquisition of an improbable glycine to arginine mutation at position 57 in the heavy chain initiates the development of heterologous neutralization breadth (Bonsignori et al, 2017a).…”

Neutralizing Antibodies Targeting HIV-1 gp41

“…A number of broadly neutralizing antibodies have been identified that target the conserved FP sequence ( Figure 1 A,D) at the interface of gp41 and gp120 in the native Env trimer conformation. These include human bnAb PGT151 [ 105 ], bnAb VRC34 targeting the N-terminus of FP [ 30 , 106 ] and bnAb ACS202 ( Figure 4 ) [ 107 , 108 ]. In addition to FP, these bnAbs contact other components of the native trimer as well as complex glycans at the gp120-gp41 interface.…”