# Mapping essential somatic hypermutations in a CD4-binding site bNAb informs HIV-1 vaccine design

## TL;DR

This study identifies key mutations in HIV antibodies that are important for vaccine design by analyzing how these mutations affect antibody function.

## Contribution

The study introduces a new method to identify essential mutations in HIV antibodies using variant libraries and cryo-EM structures.

## Key findings

- IOMAmin variants with fewer mutations still neutralize HIV effectively.
- Cryo-EM shows IOMAmin maintains key interactions with the virus despite fewer mutations.
- Mutations in specific antibody regions do not improve neutralization.

## Abstract

HIV-1 broadly neutralizing antibodies (bNAbs) targeting the CD4-binding site (CD4bs) contain rare features that pose challenges to elicit these bNAbs through vaccination. The IOMA class of CD4bs bNAbs includes fewer rare features and somatic hypermutations (SHMs) to achieve broad neutralization, thus presenting a potentially accessible pathway for vaccine-induced bNAb development. Here, we created a library of IOMA variants in which each SHM was individually reverted to the inferred germline counterpart to investigate the roles of SHMs in conferring IOMA’s neutralization potency and breadth. Impacts on neutralization for each variant were evaluated, and this information was used to design minimally mutated IOMA-class variants (IOMAmin) that incorporated the fewest SHMs required for achieving IOMA’s neutralization breadth. A cryoelectron microscopy (cryo-EM) structure of an IOMAmin variant bound to Env was used to further interpret characteristics of IOMA variants to elucidate how IOMA’s structural features correlate with its neutralization mechanism, informing the design of IOMA-targeting immunogens.

•IOMAmin variants with reduced SHMs retain neutralization potency and breadth•Cryo-EM structure reveals that IOMAmin preserves key Env interactions despite fewer SHMs•IOMA variants with mutations in CDRH3 and CDRL1 fail to improve neutralization

IOMAmin variants with reduced SHMs retain neutralization potency and breadth

Cryo-EM structure reveals that IOMAmin preserves key Env interactions despite fewer SHMs

IOMA variants with mutations in CDRH3 and CDRL1 fail to improve neutralization

Dam et al. identify essential somatic hypermutations (SHMs) in the IOMA class of CD4-binding site broadly neutralizing antibodies to guide HIV-1 vaccine design. By systematically reverting SHMs, they define minimal mutations required for IOMA’s neutralization potency and breadth. Structural and functional analyses of IOMAmin variants highlight key determinants for immunogen development.