Dependence on a variable residue limits the breadth of an HIV MPER neutralizing antibody

30 September 2022

Dr Cathrine Scheepers (right in the photo) and colleagues at the NICD published a study in PLoS Pathogens comparing CAP206-CH12 to broadly neutralizing antibodies (bNAbs) 4E10, VRC42.01 and PGZL1. All four antibodies target the membrane-proximal external region (MPER) of HIV gp41 envelope and share germline antibody genes (IGHV1-69 and IGKV3-20). Despite these similarities CAP206-CH12 has limited neutralization breadth compared to the bNAbs which can neutralize >80% of viruses.

Longitudinal sequencing of the CAP206-CH12 lineage over three years revealed similar convergent evolution towards a 111.2GW111.3 motif, known to enhance neutralization potency, among some lineage members. Mutagenesis of CAP206-CH12 from 111.2GL111.3 to 111.2GW111.3 and the introduction of the double GWGW (as seen in 4E10) motif into CAP206-CH12 modestly improved neutralization potency (2.5-3-fold) but did not reach the levels of potency of VRC42.01, 4E10 or PGZL1.

To explore the lack of potency/breadth, viral mutagenesis was performed to map the CAP206-CH12 epitope relative to the bNAbs. This indicated that CAP206-CH12 is dependent on D674, a highly variable residue at the solvent-exposed elbow of MPER. In contrast, VRC42.01, PGZL1 and 4E10 were dependent on highly conserved residues (W672, F673, T676, and W680) facing the hydrophobic patch of the MPER.

Therefore, while CAP206-CH12, VRC42.01, PGZL1 and 4E10 share germline genes and show some evidence of convergent evolution, their dependence on different amino acids, which impacts orientation of binding to the MPER, result in differences in breadth and potency. Suggesting that somatic hypermutation within shared germline genes may not provide sufficient protection within HIV vaccines directed at the MPER epitope.

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