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TitleMapping essential somatic hypermutations in a CD4-binding site bNAb informs HIV-1 vaccine design.
Journal, issue, pagesCell Rep, Vol. 44, Issue 5, Page 115713, Year 2025
Publish dateMay 15, 2025
AuthorsKim-Marie A Dam / Harry B Gristick / Yancheng E Li / Zhi Yang / Priyanthi N P Gnanapragasam / Anthony P West / Michael S Seaman / Pamela J Bjorkman /
PubMed AbstractHIV-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 ...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.
External linksCell Rep / PubMed:40378041 / PubMed Central
MethodsEM (single particle)
Resolution3.9 - 4.2 Å
Structure data

48059

9ehl

EMDB-48059, PDB-9ehl:
Structure of HIV-1 BG505 SOSIP.664 Env trimer in complex with IOMAmin5 and 10-1074 Broadly Neutralizing Antibodies - Class I
Method: EM (single particle) / Resolution: 3.9 Å

48060

9ehm

EMDB-48060, PDB-9ehm:
Structure of HIV-1 BG505 SOSIP.664 Env trimer in complex with IOMAmin5 and 10-1074 Broadly Neutralizing Antibodies - Class II
Method: EM (single particle) / Resolution: 4.2 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • human immunodeficiency virus 1
  • homo sapiens (human)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / HIV-1 / Env / bNAb / VIRAL PROTEIN-IMMUNE SYSTEM complex

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