8e1p
Crystal structure of BG505 SOSIP.v4.1-GT1.2 trimer in complex with gl-PGV20 and PGT124 Fabs
Structural highlights
FunctionQ2N0S6_9HIV1 The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface (By similarity).[RuleBase:RU004292][SAAS:SAAS000328_004_020447] The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves (By similarity).[SAAS:SAAS000328_004_240990] Publication Abstract from PubMedTargeting germline (gl-) precursors of broadly neutralizing antibodies (bNAbs) is acknowledged as an important strategy for HIV-1 vaccines. The VRC01-class of bNAbs is attractive because of its distinct genetic signature. However, VRC01-class bNAbs often require extensive somatic hypermutation, including rare insertions and deletions. We describe a BG505 SOSIP trimer, termed GT1.2, to optimize binding to gl-CH31, the unmutated common precursor of the CH30-34 bNAb lineage that acquired a large CDRH1 insertion. The GT1.2 trimer activates gl-CH31 naive B cells in knock-in mice, and B cell responses could be matured by selected boosting immunogens to generate cross-reactive Ab responses. Next-generation B cell sequencing reveals selection for VRC01-class mutations, including insertions in CDRH1 and FWR3 at positions identical to VRC01-class bNAbs, as well as CDRL1 deletions and/or glycine substitutions to accommodate the N276 glycan. These results provide proof of concept for vaccine-induced affinity maturation of B cell lineages that require rare insertions and deletions. Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions.,Caniels TG, Medina-Ramirez M, Zhang J, Sarkar A, Kumar S, LaBranche A, Derking R, Allen JD, Snitselaar JL, Capella-Pujol J, Sanchez 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. 2023 Apr 18;4(4):101003. doi: 10.1016/j.xcrm.2023.101003. Epub 2023 , Apr 11. PMID:37044090[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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