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Crystal structure of the ADCC-Potent Antibody N60-I3 Fab in complex with HIV-1 Clade A/E gp120 and M48u1
Structural highlights
FunctionQ0ED31_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). Publication Abstract from PubMedAccumulating evidence indicates a role for Fc receptor (FcR)-mediated effector functions of antibodies, including antibody-dependent cell-mediated cytotoxicity (ADCC), in prevention of HIV-1 acquisition and in post-infection control of viremia. Consequently, an understanding of the molecular basis for Env epitopes that constitute effective ADCC targets is of fundamental interest for humoral anti-HIV-1 immunity and for HIV-1 vaccine design. A substantial portion of FcR-effector function of potentially protective anti-HIV-1 antibodies is directed toward non-neutralizing, transitional, CD4-induceable (CD4i) epitopes associated with the gp41 reactive region of gp120 (Cluster A epitopes). Our previous studies defined the A32-like epitope within the Cluster A region and mapped it to the highly conserved and mobile layers 1 and 2 of the gp120 inner domain within C1-C2 regions of gp120. Here we elucidate additional Cluster A epitope structures, including an A32-like epitope, recognized by human mAb N60-i3 and a hybrid A32-C11-like epitope, recognized by rhesus macaque mAb JR4. These studies define for the first time a hybrid A32-C11-like epitope and map it to elements of both the A32-like sub-region and the 7 layered beta-sheet of the gp41-interactive region of gp120. These studies provide additional evidence that effective antibody-dependent effector function to the Cluster A region depends on precise epitope targeting - a combination of epitope footprint and mode of antibody attachment. All together these findings help in understanding how Cluster A epitopes are targeted by humoral responses IMPORTANCE: HIV/AIDS has claimed the lives of over 30 million people. Although antiretroviral drugs can control viral replication no vaccine has yet been developed to prevent the spread of the disease. Studies of natural HIV-1 infection, SIV or SHIV infected non-human primates (NHPs) and HIV-1-infected humanized mice models, passive transfer studies in infants born to HIV-infected mothers and the RV144 clinical trial have linked FcR-mediated effector functions of anti-HIV-1 antibodies with post-infection control of viremia and/or blocking viral acquisition. With this report we provide additional definition of the molecular determinants for Env antigen engagement which lead to effective antibody-dependent effector function directed to the non-neutralizing CD4-dependent epitopes in the gp41 reactive region of gp120. These findings have important implications for the development of an effective HIV-1 vaccine. Co-crystal structures of antibody N60-i3 and antibody JR4 in complex with gp120 define more Cluster A epitopes involved in effective antibody-dependent effector function against HIV-1.,Gohain N, Tolbert WD, Acharya P, Yu L, Liu T, Zhao P, Orlandi C, Visciano ML, Kamin-Lewis R, Sajadi MM, Martin L, Robinson JE, Kwong PD, DeVico AL, Ray K, Lewis GK, Pazgier M J Virol. 2015 Jun 17. pii: JVI.01232-15. PMID:26085162[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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