7t75 Citations

Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors.

Abstract

Broadly neutralizing antibodies (bnAbs) to the HIV envelope (Env) V2-apex region are important leads for HIV vaccine design. Most V2-apex bnAbs engage Env with an uncommonly long heavy-chain complementarity-determining region 3 (HCDR3), suggesting that the rarity of bnAb precursors poses a challenge for vaccine priming. We created precursor sequence definitions for V2-apex HCDR3-dependent bnAbs and searched for related precursors in human antibody heavy-chain ultradeep sequencing data from 14 HIV-unexposed donors. We found potential precursors in a majority of donors for only two long-HCDR3 V2-apex bnAbs, PCT64 and PG9, identifying these bnAbs as priority vaccine targets. We then engineered ApexGT Env trimers that bound inferred germlines for PCT64 and PG9 and had higher affinities for bnAbs, determined cryo-EM structures of ApexGT trimers complexed with inferred-germline and bnAb forms of PCT64 and PG9, and developed an mRNA-encoded cell-surface ApexGT trimer. These methods and immunogens have promise to assist HIV vaccine development.

Articles - 7t75 mentioned but not cited (1)

  1. Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors. Willis JR, Berndsen ZT, Ma KM, Steichen JM, Schiffner T, Landais E, Liguori A, Kalyuzhniy O, Allen JD, Baboo S, Omorodion O, Diedrich JK, Hu X, Georgeson E, Phelps N, Eskandarzadeh S, Groschel B, Kubitz M, Adachi Y, Mullin TM, Alavi NB, Falcone S, Himansu S, Carfi A, Wilson IA, Yates JR, Paulson JC, Crispin M, Ward AB, Schief WR. Immunity 55 2149-2167.e9 (2022)


Reviews citing this publication (5)

  1. An Overview of Human Anti-HIV-1 Neutralizing Antibodies against Diverse Epitopes of HIV-1. Kumar S, Singh S, Luthra K. ACS Omega 8 7252-7261 (2023)
  2. Influence of glycosylation on the immunogenicity and antigenicity of viral immunogens. Newby ML, Allen JD, Crispin M. Biotechnol Adv 70 108283 (2024)
  3. Beyond glycan barriers: non-cognate ligands and protein mimicry approaches to elicit broadly neutralizing antibodies for HIV-1. Walimbwa SI, Maly P, Kafkova LR, Raska M. J Biomed Sci 31 83 (2024)
  4. Structure and Dynamics Guiding Design of Antibody Therapeutics and Vaccines. Fernández-Quintero ML, Pomarici ND, Fischer AM, Hoerschinger VJ, Kroell KB, Riccabona JR, Kamenik AS, Loeffler JR, Ferguson JA, Perrett HR, Liedl KR, Han J, Ward AB. Antibodies (Basel) 12 67 (2023)
  5. The D Gene in CDR H3 Determines a Public Class of Human Antibodies to SARS-CoV-2. Yuan M, Wilson IA. Vaccines (Basel) 12 467 (2024)

Articles citing this publication (9)