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Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors.
<div class='caption-title'>Human antibody repertoire analysis guides V2-apex germline-targeting immunogen design</div>
<div class='caption-title'>Analysis of precursor frequency and HCDR3 distance to bnAb identifies PCT64 as best and PG9/16 as second-best targets for vaccine design</div>
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
OpenAccess logo Immunity (2022)
Related entries: 7t73, 7t74, 7t76, 7t77, 7ti6

Cited: 15 times
EuropePMC logo PMID: 36179689

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)

  1. Membrane-bound mRNA immunogens lower the threshold to activate HIV Env V2 apex-directed broadly neutralizing B cell precursors in humanized mice. Melzi E, Willis JR, Ma KM, Lin YC, Kratochvil S, Berndsen ZT, Landais EA, Kalyuzhniy O, Nair U, Warner J, Steichen JM, Kalyuzhniy A, Le A, Pecetta S, Perez M, Kirsch K, Weldon SR, Falcone S, Himansu S, Carfi A, Sok D, Ward AB, Schief WR, Batista FD. Immunity 55 2168-2186.e6 (2022)
  2. Vaccination induces broadly neutralizing antibody precursors to HIV gp41. Schiffner T, Phung I, Ray R, Irimia A, Tian M, Swanson O, Lee JH, Lee CD, Marina-Zárate E, Cho SY, Huang J, Ozorowski G, Skog PD, Serra AM, Rantalainen K, Allen JD, Baboo S, Rodriguez OL, Himansu S, Zhou J, Hurtado J, Flynn CT, McKenney K, Havenar-Daughton C, Saha S, Shields K, Schultze S, Smith ML, Liang CH, Toy L, Pecetta S, Lin YC, Willis JR, Sesterhenn F, Kulp DW, Hu X, Cottrell CA, Zhou X, Ruiz J, Wang X, Nair U, Kirsch KH, Cheng HL, Davis J, Kalyuzhniy O, Liguori A, Diedrich JK, Ngo JT, Lewis V, Phelps N, Tingle RD, Spencer S, Georgeson E, Adachi Y, Kubitz M, Eskandarzadeh S, Elsliger MA, Amara RR, Landais E, Briney B, Burton DR, Carnathan DG, Silvestri G, Watson CT, Yates JR, Paulson JC, Crispin M, Grigoryan G, Ward AB, Sok D, Alt FW, Wilson IA, Batista FD, Crotty S, Schief WR. Nat Immunol 25 1073-1082 (2024)
  3. Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates. He W, Ou T, Skamangas N, Bailey CC, Bronkema N, Guo Y, Yin Y, Kobzarenko V, Zhang X, Pan A, Liu X, Xu J, Zhang L, Allwardt AE, Mitra D, Quinlan B, Sanders RW, Choe H, Farzan M. Immunity 56 2408-2424.e6 (2023)
  4. Hydrogen-Deuterium Exchange Epitope Mapping of Glycosylated Epitopes Enabled by Online Immobilized Glycosidase. O'Leary TR, Balasubramaniam D, Hughes K, Foster D, Boyles J, Coleman K, Griffin PR. Anal Chem 95 10204-10210 (2023)
  5. Affinity gaps among B cells in germinal centers drive the selection of MPER precursors. Ray R, Schiffner T, Wang X, Yan Y, Rantalainen K, Lee CD, Parikh S, Reyes RA, Dale GA, Lin YC, Pecetta S, Giguere S, Swanson O, Kratochvil S, Melzi E, Phung I, Madungwe L, Kalyuzhniy O, Warner J, Weldon SR, Tingle R, Lamperti E, Kirsch KH, Phelps N, Georgeson E, Adachi Y, Kubitz M, Nair U, Crotty S, Wilson IA, Schief WR, Batista FD. Nat Immunol 25 1083-1096 (2024)
  6. Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response. Patel A, Kumar S, Lai L, Chakravarthy C, Valanparambil R, Reddy ES, Gottimukkala K, Bajpai P, Raju DR, Edara VV, Davis-Gardner ME, Linderman S, Dixit K, Sharma P, Mantus G, Cheedarla N, Verkerke HP, Frank F, Neish AS, Roback JD, Davis CW, Wrammert J, Ahmed R, Suthar MS, Sharma A, Murali-Krishna K, Chandele A, Ortlund EA. Structure 31 801-811.e5 (2023)
  7. Recognition determinants of improved HIV-1 neutralization by a heavy chain matured pediatric antibody. Kumar S, Singh S, Chatterjee A, Bajpai P, Sharma S, Katpara S, Lodha R, Dutta S, Luthra K. iScience 26 107579 (2023)
  8. RAIN: machine learning-based identification for HIV-1 bNAbs. Foglierini M, Nortier P, Schelling R, Winiger RR, Jacquet P, O'Dell S, Demurtas D, Mpina M, Lweno O, Muller YD, Petrovas C, Daubenberger C, Perreau M, Doria-Rose NA, Gottardo R, Perez L. Nat Commun 15 5339 (2024)
  9. Vaccine priming of rare HIV broadly neutralizing antibody precursors in nonhuman primates. Steichen JM, Phung I, Salcedo E, Ozorowski G, Willis JR, Baboo S, Liguori A, Cottrell CA, Torres JL, Madden PJ, Ma KM, Sutton HJ, Lee JH, Kalyuzhniy O, Allen JD, Rodriguez OL, Adachi Y, Mullen TM, Georgeson E, Kubitz M, Burns A, Barman S, Mopuri R, Metz A, Altheide TK, Diedrich JK, Saha S, Shields K, Schultze SE, Smith ML, Schiffner T, Burton DR, Watson CT, Bosinger SE, Crispin M, Yates JR, Paulson JC, Ward AB, Sok D, Crotty S, Schief WR. Science 384 eadj8321 (2024)


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