6dfg | pdb_00006dfg
BG505 MD39 SOSIP trimer in complex with mature BG18 fragment antigen binding
Structural highlights
Function[Q2N0S6_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] [Q2N0S8_9HIV1] Envelope glycoprotein gp160: Oligomerizes in the host endoplasmic reticulum into predominantly trimers. In a second time, gp160 transits in the host Golgi, where glycosylation is completed. The precursor is then proteolytically cleaved in the trans-Golgi and thereby activated by cellular furin or furin-like proteases to produce gp120 and gp41.[HAMAP-Rule:MF_04083] Surface protein gp120: Attaches the virus to the host lymphoid cell by binding to the primary receptor CD4. This interaction induces a structural rearrangement creating a high affinity binding site for a chemokine coreceptor like CXCR4 and/or CCR5. Acts as a ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on endothelial cells of liver sinusoids and lymph node sinuses. These interactions allow capture of viral particles at mucosal surfaces by these cells and subsequent transmission to permissive cells. HIV subverts the migration properties of dendritic cells to gain access to CD4+ T-cells in lymph nodes. Virus transmission to permissive T-cells occurs either in trans (without DCs infection, through viral capture and transmission), or in cis (following DCs productive infection, through the usual CD4-gp120 interaction), thereby inducing a robust infection. In trans infection, bound virions remain infectious over days and it is proposed that they are not degraded, but protected in non-lysosomal acidic organelles within the DCs close to the cell membrane thus contributing to the viral infectious potential during DCs' migration from the periphery to the lymphoid tissues. On arrival at lymphoid tissues, intact virions recycle back to DCs' cell surface allowing virus transmission to CD4+ T-cells.[HAMAP-Rule:MF_04083] Transmembrane protein gp41: Acts as a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During fusion of viral and target intracellular membranes, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Complete fusion occurs in host cell endosomes and is dynamin-dependent, however some lipid transfer might occur at the plasma membrane. The virus undergoes clathrin-dependent internalization long before endosomal fusion, thus minimizing the surface exposure of conserved viral epitopes during fusion and reducing the efficacy of inhibitors targeting these epitopes. Membranes fusion leads to delivery of the nucleocapsid into the cytoplasm.[HAMAP-Rule:MF_04083] Publication Abstract from PubMedVaccine induction of broadly neutralizing antibodies (bnAbs) to human immunodeficiency virus (HIV) remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity determining region 3 (HCDR3) is a major barrier. Exploiting ultra-deep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer-based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model, and in ex-vivo screens bound a range of potential bnAb-precursor human naive B cells. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs, and could be applied to most HCDR3-dominant antibodies from other pathogens. A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses.,Steichen JM, Lin YC, Havenar-Daughton C, Pecetta S, Ozorowski G, Willis JR, Toy L, Sok D, Liguori A, Kratochvil S, Torres JL, Kalyuzhniy O, Melzi E, Kulp DW, Raemisch S, Hu X, Bernard SM, Georgeson E, Phelps N, Adachi Y, Kubitz M, Landais E, Umotoy J, Robinson A, Briney B, Wilson IA, Burton DR, Ward AB, Crotty S, Batista FD, Schief WR Science. 2019 Oct 31. pii: science.aax4380. doi: 10.1126/science.aax4380. PMID:31672916[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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