Browsing by Author "Nicely, Nathan I"

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    Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies.
    (Cell, 2021-05-18) Williams, Wilton B; Meyerhoff, R Ryan; Edwards, RJ; Li, Hui; Manne, Kartik; Nicely, Nathan I; Henderson, Rory; Zhou, Ye; Janowska, Katarzyna; Mansouri, Katayoun; Gobeil, Sophie; Evangelous, Tyler; Hora, Bhavna; Berry, Madison; Abuahmad, A Yousef; Sprenz, Jordan; Deyton, Margaret; Stalls, Victoria; Kopp, Megan; Hsu, Allen L; Borgnia, Mario J; Stewart-Jones, Guillaume BE; Lee, Matthew S; Bronkema, Naomi; Moody, M Anthony; Wiehe, Kevin; Bradley, Todd; Alam, S Munir; Parks, Robert J; Foulger, Andrew; Oguin, Thomas; Sempowski, Gregory D; Bonsignori, Mattia; LaBranche, Celia C; Montefiori, David C; Seaman, Michael; Santra, Sampa; Perfect, John; Francica, Joseph R; Lynn, Geoffrey M; Aussedat, Baptiste; Walkowicz, William E; Laga, Richard; Kelsoe, Garnett; Saunders, Kevin O; Fera, Daniela; Kwong, Peter D; Seder, Robert A; Bartesaghi, Alberto; Shaw, George M; Acharya, Priyamvada; Haynes, Barton F
    Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.
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    Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques.
    (PLoS Pathog, 2015-08) Santra, Sampa; Tomaras, Georgia D; Warrier, Ranjit; Nicely, Nathan I; Liao, Hua-Xin; Pollara, Justin; Liu, Pinghuang; Alam, S Munir; Zhang, Ruijun; Cocklin, Sarah L; Shen, Xiaoying; Duffy, Ryan; Xia, Shi-Mao; Schutte, Robert J; Pemble Iv, Charles W; Dennison, S Moses; Li, Hui; Chao, Andrew; Vidnovic, Kora; Evans, Abbey; Klein, Katja; Kumar, Amit; Robinson, James; Landucci, Gary; Forthal, Donald N; Montefiori, David C; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Pitisuttithum, Punnee; Rerks-Ngarm, Supachai; Robb, Merlin L; Michael, Nelson L; Kim, Jerome H; Soderberg, Kelly A; Giorgi, Elena E; Blair, Lily; Korber, Bette T; Moog, Christiane; Shattock, Robin J; Letvin, Norman L; Schmitz, Joern E; Moody, MA; Gao, Feng; Ferrari, Guido; Shaw, George M; Haynes, Barton F
    HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.
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    Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies.
    (J Exp Med, 2013-02-11) Yang, Guang; Holl, T Matt; Liu, Yang; Li, Yi; Lu, Xiaozhi; Nicely, Nathan I; Kepler, Thomas B; Alam, S Munir; Liao, Hua-Xin; Cain, Derek W; Spicer, Leonard; VandeBerg, John L; Haynes, Barton F; Kelsoe, Garnett
    Many human monoclonal antibodies that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to mammalian autoantigens. Indeed, the generation of neutralizing antibodies to the 2F5 and 4E10 epitopes of HIV-1 gp41 in man may be proscribed by immune tolerance because mice expressing the V(H) and V(L) regions of 2F5 have a block in B cell development that is characteristic of central tolerance. This developmental blockade implies the presence of tolerizing autoantigens that are mimicked by the membrane-proximal external region of HIV-1 gp41. We identify human kynureninase (KYNU) and splicing factor 3b subunit 3 (SF3B3) as the primary conserved, vertebrate self-antigens recognized by the 2F5 and 4E10 antibodies, respectively. 2F5 binds the H4 domain of KYNU which contains the complete 2F5 linear epitope (ELDKWA). 4E10 recognizes an epitope of SF3B3 that is strongly dependent on hydrophobic interactions. Opossums carry a rare KYNU H4 domain that abolishes 2F5 binding, but they retain the SF3B3 4E10 epitope. Immunization of opossums with HIV-1 gp140 induced extraordinary titers of serum antibody to the 2F5 ELDKWA epitope but little or nothing to the 4E10 determinant. Identification of structural motifs shared by vertebrates and HIV-1 provides direct evidence that immunological tolerance can impair humoral responses to HIV-1.
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    Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations.
    (Nature communications, 2017-11-23) Williams, Wilton B; Zhang, Jinsong; Jiang, Chuancang; Nicely, Nathan I; Fera, Daniela; Luo, Kan; Moody, M Anthony; Liao, Hua-Xin; Alam, S Munir; Kepler, Thomas B; Ramesh, Akshaya; Wiehe, Kevin; Holland, James A; Bradley, Todd; Vandergrift, Nathan; Saunders, Kevin O; Parks, Robert; Foulger, Andrew; Xia, Shi-Mao; Bonsignori, Mattia; Montefiori, David C; Louder, Mark; Eaton, Amanda; Santra, Sampa; Scearce, Richard; Sutherland, Laura; Newman, Amanda; Bouton-Verville, Hilary; Bowman, Cindy; Bomze, Howard; Gao, Feng; Marshall, Dawn J; Whitesides, John F; Nie, Xiaoyan; Kelsoe, Garnett; Reed, Steven G; Fox, Christopher B; Clary, Kim; Koutsoukos, Marguerite; Franco, David; Mascola, John R; Harrison, Stephen C; Haynes, Barton F; Verkoczy, Laurent
    A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. Here, we report host tolerance mechanisms that limit the development of CD4-binding site (CD4bs), HCDR3-binder bnAbs via sequential HIV-1 Env vaccination. Vaccine-induced macaque CD4bs antibodies neutralize 7% of HIV-1 strains, recognize open Env trimers, and accumulate relatively modest somatic mutations. In naive CD4bs, unmutated common ancestor knock-in mice Env+B cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env- upon receptor editing. In comparison with repetitive Env immunizations, sequential Env administration rescue anergic Env+ (non-edited) precursor B cells. Thus, stepwise immunization initiates CD4bs-bnAb responses, but immune tolerance mechanisms restrict their development, suggesting that sequential immunogen-based vaccine regimens will likely need to incorporate strategies to expand bnAb precursor pools.