8sw3 | pdb_00008sw3
BG505 GT1.1 SOSIP in complex with NHP Fabs 12C11 and RM20A3
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 PubMedEliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)-specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers. Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site.,Caniels TG, Medina-Ramirez M, Zhang S, Kratochvil S, Xian Y, Koo JH, Derking R, Samsel J, van Schooten J, Pecetta S, Lamperti E, Yuan M, Carrasco MR, Del Moral Sanchez I, Allen JD, Bouhuijs JH, Yasmeen A, Ketas TJ, Snitselaar JL, Bijl TPL, Martin IC, Torres JL, Cupo A, Shirreff L, Rogers K, Mason RD, Roederer M, Greene KM, Gao H, Silva CM, Baken IJL, Tian M, Alt FW, Pulendran B, Seaman MS, Crispin M, van Gils MJ, Montefiori DC, McDermott AB, Villinger FJ, Koup RA, Moore JP, Klasse PJ, Ozorowski G, Batista FD, Wilson IA, Ward AB, Sanders RW Sci Immunol. 2024 Aug 30;9(98):eadk9550. doi: 10.1126/sciimmunol.adk9550. Epub , 2024 Aug 30. PMID:39213338[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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