6mn7
Cryo-EM structure of BG505.SOSIP.664 in complex with BF520.1 antigen binding fragment
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 PubMedHIV-infected infants develop broadly neutralizing plasma responses with more rapid kinetics than adults, suggesting the ontogeny of infant responses could better inform a path to achievable vaccine targets. Here we reconstruct the developmental lineage of BF520.1, an infant-derived HIV-specific broadly neutralizing antibody (bnAb), using computational methods developed specifically for this purpose. We find that the BF520.1 inferred naive precursor binds HIV Env. We also show that heterologous cross-clade neutralizing activity evolved in the infant within six months of infection and that, ultimately, only 2% SHM is needed to achieve the full breadth of the mature antibody. Mutagenesis and structural analyses reveal that, for this infant bnAb, substitutions in the kappa chain were critical for activity, particularly in CDRL1. Overall, the developmental pathway of this infant antibody includes features distinct from adult antibodies, including several that may be amenable to better vaccine responses. Kappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage.,Simonich CA, Doepker L, Ralph D, Williams JA, Dhar A, Yaffe Z, Gentles L, Small CT, Oliver B, Vigdorovich V, Mangala Prasad V, Nduati R, Sather DN, Lee KK, Matsen Iv FA, Overbaugh J Nat Commun. 2019 May 16;10(1):2190. doi: 10.1038/s41467-019-09481-7. PMID:31097697[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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