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    Induction of Fc-Mediated Effector Functions against a Stabilized Inner Domain of HIV-1 gp120 Designed to Selectively Harbor the A32 Epitope Region

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    Author
    Visciano, M.L.
    Gohain, N.
    Sherburn, R.
    Date
    2019
    Journal
    Frontiers in Immunology
    Publisher
    Frontiers Media S.A.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3389/fimmu.2019.00677
    Abstract
    Recent clinical trials and studies using nonhuman primates (NHPs) suggest that antibody-mediated protection against HIV-1 will require α-HIV envelope humoral immunity beyond direct neutralization to include Fc-receptor (FcR) mediated effector functions such as antibody-dependent cellular cytotoxicity (ADCC). There is also strong evidence indicating that the most potent ADCC response in humans is directed toward transitional non-neutralizing epitopes associated with the gp41-interactive face of gp120, particularly those within the first and second constant (C1–C2) region (A32-like epitopes). These epitopes were shown to be major targets of ADCC responses during natural infection and have been implicated in vaccine-induced protective immunity. Here we describe the immunogenicity of ID2, an immunogen consisting of the inner domain of the clade A/E 93TH057 HIV-1 gp120 expressed independently of the outer domain (OD) and stabilized in the CD4-bound conformation to harbor conformational A32 region epitopes within a minimal structural unit of HIV-1 Env. ID2 induced A32-specific antibody responses in BALB/c mice when injected alone or in the presence of the adjuvants Alum or GLA-SE. Low α-ID2 titers were detected in mice immunized with ID2 alone whereas robust responses were observed with ID2 plus adjuvant, with the greatest ID2 and A32-specific titers observed in the GLA-SE group. Only sera from groups immunized in the presence of GLA-SE were capable of mediating significant ADCC using NKr cells sensitized with recombinant BaL gp120 as targets and human PBMCs as effectors. A neutralization response to a tier 2 virus was not observed. Altogether, our studies demonstrate that ID2 is highly immunogenic and elicits A32-specific ADCC responses in an animal host. The ID2 immunogen has significant translational value as it can be used in challenge studies to evaluate the role of non-neutralizing antibodies directed at the A32 subregion in HIV-1 protection. Copyright 2019 The Authors.
    Sponsors
    This work was supported by NIH Grants: NIAID R01 AI116274 to MP, R01AI129769 to MP and Andres Finzi and NIAID P01 AI120756 to Georgia Tomaras.
    Keyword
    A32 epitope
    ADCC (Antibody dependent cellular cytotoxicity)
    Fc-mediated effector function
    HIV envelope
    ID (Inner domain) immunogen
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85065024752&doi=10.3389%2ffimmu.2019.00677&partnerID=40&md5=de9299640a61bbf05d4f1294c7692ced; http://hdl.handle.net/10713/10665
    ae974a485f413a2113503eed53cd6c53
    10.3389/fimmu.2019.00677
    Scopus Count
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    UMB Open Access Articles 2019

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