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    Home > Active Ingredient News > Immunology News > Cell's important finding: The presence of type I natural antibodies similar to 2G12 antibodies in the human body may become a new target for HIV-1 vaccines

    Cell's important finding: The presence of type I natural antibodies similar to 2G12 antibodies in the human body may become a new target for HIV-1 vaccines

    • Last Update: 2021-06-22
    • Source: Internet
    • Author: User
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    Written by | Original editor | A variety of pathogens, including the envelope protein of HIV [1], yeast [2] (Hall and Gow, 2013), and the surface of the spike protein of SARS-CoV-2 (Watanabe et al.
    , 2020) All have glycosylation modification
    .

    Antibodies that recognize glycosylation in the body are a series of natural antibodies that existed before the body was stimulated by the same type of antigen
    .

    They exist in different subtypes and provide the body with the first line of defense against external bacterial, fungal and viral infections [3] (Holodick et al.
    , 2017)
    .

    In the human body, natural antibodies produce mutant antibodies or some unknown changes after being stimulated by antigens, such as the way IgM antibodies change in pre-immune B cells [3].
    It is currently assumed to be B cells from the marginal zone or transitional period [3] 4]
    .

    The envelope protein (Env) of HIV-1 (HIV-1) has severe glycosylation, and the recognition of epitopes recognized by the broadly neutralizing antibody (bnAb) by antibodies is restricted [1] (Cao et al.
    al.
    , 2017)
    .

    The bnAb of HIV-1 Env can approach the Env protein epitope through the long complementarity determining region (CDR) loop, but at the same time it also reaches a certain balance with the surrounding polysaccharides, which affects the neutralization effect [5]
    .

    Therefore, researchers have been looking for antibodies specifically against polysaccharides, trying to turn this effective defense against HIV-1 into its weakness [6]
    .

    However, the polysaccharides present in HIV-1 and other pathogens are also present in the host molecule [7].
    Therefore, antibodies induced by pathogen polysaccharides may be inhibited by the body's immune tolerance
    .

    In previous studies, the 2G12 antibody is the only example that specifically binds HIV-1 Env proteoglycan [8]
    .

    The 2G12 antibody has a relatively short CDR3 loop and a unique heavy chain variable region (VH) domain interchange (Figure 1)
    .

    Among them, the exchange of two antibody binding fragments (Fab) forms a dimerized multivalent surface of Fab, which has strong Env surface polysaccharide binding ability [9]
    .

    The Fab dimerization of the 2G12 antibody has been shown to play a vital function in binding to HIV-1, which makes it stand out from ordinary polysaccharide-binding antibodies with weaker binding capacity
    .

    The affinity of bnAb 2G12 with HIV-1 is about nM, mainly because it can multivalently recognize a unique polysaccharide cluster [10]
    .

    The results of x-ray crystallography, negative stain electron microscopy and cryo-electron microscopy (cryo-EM) jointly demonstrated the 2G12 antibody VH domain exchange and Fab dimerization, as well as its multiple polysaccharide binding sites [11]
    .

    These two characteristics are crucial to its high affinity binding to HIV-1 Env
    .

    In addition to HIV-1 Env, 2G12 can also bind to Candida albicans, because it has a similar mannose motif with HIV-1 Env polysaccharide [12]
    .

    Recently, the teams of Wilton B.
    Williams, Priyamvada Acharya and Barton F.
    Haynes of Duke University Vaccine Research Institute, Duke University Department of Medicine and Immunology and other units published a titled Fab-dimerized glycan-reactive antibodies are astructural category on Cell.
    of natural antibodies, in which the author reported multiple Fab-dimerized glycan-reactive (FDG) HIV-1 Env antibodies with natural Fab dimerization, which have a type I conformation similar to 2G12.
    Different from the Y-shaped conformation of ordinary antibodies
    .

    However, they do not require the exchange of VH domains to neutralize HIV-1
    .

    In addition to recognizing yeast and HIV-1 Env polysaccharides, FDG antibody can also recognize the S2 subunit of the spike protein of SARS-CoV-2
    .

    First, the author used a glycosylated polypeptide (Man9-V3) to mimic the natural HIV-1 Env trimer to immunize rhesus monkeys, and then isolated four DH717 lineage antibodies DH717.
    1 and DH717 from their plasma.
    .
    2, DH717.
    3 and DH717.
    4
    .

    These antibodies can recognize the recombinant Env soluble trisomy of HIV-1, Candida albicans and Cryptococcus neoformans, and have a stronger affinity than the 2G12 antibody
    .

    Their recognition of Man9-V3 is based on its polysaccharide motif rather than the polypeptide sequence itself
    .

    Under the negative staining electron microscope (NSEM), it can be seen that the three antibody subtypes DH717.
    1, DH717.
    2, and DH717.
    4 have the classic Y-type and special I-type two conformations
    .

    The type I conformation, which is similar to the conformation of the 2G12 antibody, is formed due to the dimerization of Fab and is called FDG (Fab-dimerized glycan-reactive, FDG) antibody
    .

    It's just that the two Fab regions of the 2G12 antibody are juxtaposed on the same plane relative to the Fc, while the two Fab fragments of the H717 I antibody are not on the same plane relative to the Fc, but are deflected by an angle of 90°
    .

    At the same time, this FDG antibody does not have the VH domain interchange phenomenon similar to 2G12
    .

    Subsequently, this result was verified by the analysis of the crystal structure
    .

    It also explains that the dimerization of Fab is mediated by several mechanisms, including disulfide bonds, hydrophobic interactions and hydrogen bonds formed between Fab-Fab
    .

    Among them, the additional disulfide bond formed at the C74 position relative to ordinary antibodies dominates the dimerization of Fab and the formation of the I-type conformation
    .

    Subsequently, the authors used transcriptome sequencing to group and trace the B cells in the blood of rhesus monkeys, and found that the B cells that produce this type I antibody that binds to polysaccharides exist before immunization, and at least they mature and expand after being stimulated.
    Increase
    .

    This phenomenon has also been verified in the human body
    .

    Precursor FDG antibodies have been isolated from HIV-1 seronegative humans, and they are present in the marginal zone B cells of IgM+IgD+CD27+
    .

    It shows that this kind of antibody also exists naturally in the human body
    .

    This research result may provide a new target for HIV-1 vaccine research
    .

    The author only tested the reactivity of this FDG antibody to recombinant HIV-1 Env and SARS-CoV-2 S proteoglycans, but this may exclude other types of polysaccharide forms in the body
    .

    The article tested the precursor FDG antibodies in the peripheral blood of 9 individuals who were not infected with HIV-1.
    In the future, individuals and other immune organizations that need to be in a larger group will conduct more in-depth research on the information of these Abs
    .

    Original link: https://doi.
    org/10.
    1016/j.
    cell.
    2021.
    04.
    042 Platemaker: 11 References 1.
    Cao, L.
    , Diedrich, JK, Kulp, DW, Pauthner, M.
    , He, L .
    , Park, SR, Sok, D.
    , Su, CY, Delahunty, CM, Menis, S.
    , et al.
    (2017).
    Global site-specific N-glycosylation analysis of HIV envelope glycoprotein.
    Nat.
    Commun.
    8, 14954.
    2.
    Hall, RA, and Gow, NA (2013).
    Mannosylation in Candida albicans: role in cell wall function and immune recognition.
    Mol.
    Microbiol.
    90, 1147–1161.
    3.
    Holodick, NE, Rodrı´guez-Zhurbenko, N.
    , and Herna´ ndez, AM (2017).
    Defining Natural Antibodies.
    Front.
    Immunol.
    8, 872.
    4.
    Qua´ ch, TD, Rodrı´guez-Zhurbenko, N.
    , Hopkins, TJ, Guo, X.
    , Herna´ ndez , AM, Li, W.
    , and Rothstein, TL (2016).
    Distinctions among Circulating Antibody-Secreting Cell Populations, Including B-1 Cells, in Human Adult Peripheral Blood.
    J.
    Immunol.
    196, 1060–1069.
    5.
    Fera, D .
    , Lee, MS,Wiehe, K.
    , Meyerhoff, RR, Piai, A.
    , Bonsignori, M.
    , Aussedat, B.
    , Walkowicz, WE, Ton, T.
    , Zhou, JO, et al.
    (2018).
    HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope.
    Nat.
    Commun.
    9, 1111.
    6.
    Daniels, CN, and Saunders, KO (2019).
    Antibody responses to the HIV-1 envelope high mannose patch.
    Adv.
    Immunol.
    143, 11– 73.
    7.
    Yu, JS, Ma, BJ, Scearce, RM, Liao, HX, and Haynes, BF (2010).
    Anti-Ebola MAb 17A3 reacts with bovine and human alpha-2-macroglobulin proteins.
    J.
    Virol.
    Methods168, 248 –250.
    8.
    Calarese, DA, Scanlan, CN, Zwick, MB, Deechongkit, S.
    , Mimura, Y.
    , Kunert, R.
    , Zhu, P.
    , Wormald, MR, Stanfield, RL, Roux, KH, et al.
    (2003).
    Antibody domain exchange is an immunological solution to carbohydrate cluster recognition.
    Science300, 2065–2071.
    9.
    Murin, CD, Julien, JP, Sok,D.
    , Stanfield, RL, Khayat, R.
    , Cupo, A.
    , Moore, JP, Burton, DR, Wilson, IA, and Ward, AB (2014).
    Structure of 2G12 Fab2 in complex with soluble and fully glycosylated HIV- 1 Env by negative-stain single-particle electron microscopy.
    J.
    Virol.
    88, 10177–10188.
    10.
    Scanlan, CN, Pantophlet, R.
    , Wormald, MR, Ollmann Saphire, E.
    , Stanfield, R.
    , Wilson, IA, Katinger, H.
    , Dwek, RA, Rudd, PM, and Burton, DR (2002).
    The broadly neutralizing anti-human immunodeficiency virus type 1 antibody 2G12 recognizes a cluster of alpha1-->2 mannose residues on the outer face of gp120.
    J.
    Virol.
    76, 7306–7321.
    11.
    Seabright, GE, Cottrell, CA, van Gils, MJ, D'addabbo, A.
    , Harvey, DJ, Behrens, AJ, Allen, JD, Watanabe, Y.
    , Scaringi, N .
    , Polveroni, TM, et al.
    (2020).
    Networks of HIV-1 Envelope Glycans Maintain Antibody Epitopes in the Face of Glycan Additions and Deletions.
    Structure28, 897–909.
    e6.
    12.
    Doores, KJ, Fulton, Z.
    , Huber, M.
    , Wilson, IA, and Burton, DR (2010b).
    Antibody 2G12 recognizes di-mannose equivalently in domain- and nondomainexchanged forms but only binds the HIV-1 glycan shield if domain exchanged.
    J.
    Virol.
    84, 10690-10699.
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