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HIV-1 CD4-binding site germline antibody-Env structures inform vaccine design.

<div class='caption-title'>BG24iGLs bind the CD4bs of the GT1 immunogen.</div>
<div class='caption-title'>Comparison of BG24iGL and BG24mat CD4bs epitopes.</div>
<div class='caption-title'>Somatic hypermutation and germline features play a role in BG24 recognition of the CD4bs interface.</div>
Dam KA, Barnes CO, Gristick HB, Schoofs T, Gnanapragasam PNP, Nussenzweig MC, Bjorkman PJ
OpenAccess logo Nat Commun 13 6123 (2022)
Related entries: 7ugm, 7ugn, 7ugo, 7ugp

Cited: 4 times
EuropePMC logo PMID: 36253376

Abstract

BG24, a VRC01-class broadly neutralizing antibody (bNAb) against HIV-1 Env with relatively few somatic hypermutations (SHMs), represents a promising target for vaccine strategies to elicit CD4-binding site (CD4bs) bNAbs. To understand how SHMs correlate with BG24 neutralization of HIV-1, we report 4.1 Å and 3.4 Å single-particle cryo-EM structures of two inferred germline (iGL) BG24 precursors complexed with engineered Env-based immunogens lacking CD4bs N-glycans. Structures reveal critical Env contacts by BG24iGL and identify antibody light chain structural features that impede Env recognition. In addition, biochemical data and cryo-EM structures of BG24iGL variants bound to Envs with CD4bs glycans present provide insights into N-glycan accommodation, including structural modes of light chain adaptations in the presence of the N276gp120 glycan. Together, these findings reveal Env regions critical for germline antibody recognition and potential sites to alter in immunogen design.

Articles citing this publication (4)

  1. CD4 binding site immunogens elicit heterologous anti-HIV-1 neutralizing antibodies in transgenic and wild-type animals. Gristick HB, Hartweger H, Loewe M, van Schooten J, Ramos V, Oliveira TY, Nishimura Y, Koranda NS, Wall A, Yao KH, Poston D, Gazumyan A, Wiatr M, Horning M, Keeffe JR, Hoffmann MAG, Yang Z, Abernathy ME, Dam KA, Gao H, Gnanapragasam PNP, Kakutani LM, Pavlovitch-Bedzyk AJ, Seaman MS, Howarth M, McGuire AT, Stamatatos L, Martin MA, West AP, Nussenzweig MC, Bjorkman PJ. Sci Immunol 8 eade6364 (2023)
  2. Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site. Banach BB, Pletnev S, Olia AS, Xu K, Zhang B, Rawi R, Bylund T, Doria-Rose NA, Nguyen TD, Fahad AS, Lee M, Lin BC, Liu T, Louder MK, Madan B, McKee K, O'Dell S, Sastry M, Schön A, Bui N, Shen CH, Wolfe JR, Chuang GY, Mascola JR, Kwong PD, DeKosky BJ. Nat Commun 14 7593 (2023)
  3. Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions. Caniels TG, Medina-Ramírez M, Zhang J, Sarkar A, Kumar S, LaBranche A, Derking R, Allen JD, Snitselaar JL, Capella-Pujol J, Sánchez IDM, Yasmeen A, Diaz M, Aldon Y, Bijl TPL, Venkatayogi S, Martin Beem JS, Newman A, Jiang C, Lee WH, Pater M, Burger JA, van Breemen MJ, de Taeye SW, Rantalainen K, LaBranche C, Saunders KO, Montefiori D, Ozorowski G, Ward AB, Crispin M, Moore JP, Klasse PJ, Haynes BF, Wilson IA, Wiehe K, Verkoczy L, Sanders RW. Cell Rep Med 4 101003 (2023)
  4. High throughput analysis of B cell dynamics and neutralizing antibody development during immunization with a novel clade C HIV-1 envelope. Mopuri R, Welbourn S, Charles T, Ralli-Jain P, Rosales D, Burton S, Aftab A, Karunakaran K, Pellegrini K, Kilembe W, Karita E, Gnanakaran S, Upadhyay AA, Bosinger SE, Derdeyn CA. PLoS Pathog 19 e1011717 (2023)


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