Broadly neutralizing anti-HIV-1 antibodies tether viral particles at the surface of infected cells.
Antibodies, Neutralizing
/ immunology
Antibody-Dependent Cell Cytotoxicity
Broadly Neutralizing Antibodies
Cell Line
Epitopes
HIV Antibodies
/ immunology
HIV Infections
/ immunology
HIV-1
/ immunology
Host Microbial Interactions
/ immunology
Humans
T-Lymphocytes
Virion
/ immunology
env Gene Products, Human Immunodeficiency Virus
/ immunology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 02 2022
02 02 2022
Historique:
received:
09
06
2021
accepted:
17
01
2022
entrez:
3
2
2022
pubmed:
4
2
2022
medline:
16
2
2022
Statut:
epublish
Résumé
Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) are promising molecules for therapeutic or prophylactic interventions. Beyond neutralization, bNAbs exert Fc-dependent functions including antibody-dependent cellular cytotoxicity and activation of the complement. Here, we show that a subset of bNAbs targeting the CD4 binding site and the V1/V2 or V3 loops inhibit viral release from infected cells. We combined immunofluorescence, scanning electron microscopy, transmission electron microscopy and immunogold staining to reveal that some bNAbs form large aggregates of virions at the surface of infected cells. This activity correlates with the capacity of bNAbs to bind to Env at the cell surface and to neutralize cell-free viral particles. We further show that antibody bivalency is required for viral retention, and that aggregated virions are neutralized. We have thus identified an additional antiviral activity of bNAbs, which block HIV-1 release by tethering viral particles at the surface of infected cells.
Identifiants
pubmed: 35110562
doi: 10.1038/s41467-022-28307-7
pii: 10.1038/s41467-022-28307-7
pmc: PMC8810770
doi:
Substances chimiques
Antibodies, Neutralizing
0
Broadly Neutralizing Antibodies
0
Epitopes
0
HIV Antibodies
0
env Gene Products, Human Immunodeficiency Virus
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
630Informations de copyright
© 2022. The Author(s).
Références
Mouquet, H. Antibody B cell responses in HIV-1 infection. Trends Immunol. 35, 549–561 (2014).
pubmed: 25240985
doi: 10.1016/j.it.2014.08.007
Shingai, M. et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 503, 277 (2013).
pubmed: 24172896
pmcid: 4133787
doi: 10.1038/nature12746
Barouch, D. H. et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503, 224 (2013).
pubmed: 24172905
pmcid: 4017780
doi: 10.1038/nature12744
Parsons, M. S. et al. Partial efficacy of a broadly neutralizing antibody against cell-associated SHIV infection. Sci. Transl. Med. 9, eaaf1483 (2017).
pubmed: 28794282
doi: 10.1126/scitranslmed.aaf1483
Moldt, B. et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc. Natl Acad. Sci. USA 109, 18921–18925 (2012).
pubmed: 23100539
pmcid: 3503218
doi: 10.1073/pnas.1214785109
Gautam, R. et al. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533, 105 (2016).
pubmed: 27120156
pmcid: 5127204
doi: 10.1038/nature17677
Halper-Stromberg, A. et al. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized Mice. Cell 158, 989–999 (2014).
pubmed: 25131989
pmcid: 4163911
doi: 10.1016/j.cell.2014.07.043
Hsu, D. C. et al. TLR7 agonist, N6-LS and PGT121 delayed viral rebound in SHIV-infected macaques after antiretroviral therapy interruption. PLoS Pathog. 17, e1009339 (2021).
pubmed: 33600506
pmcid: 7924766
doi: 10.1371/journal.ppat.1009339
Caskey, M., Klein, F. & Nussenzweig, M. C. Broadly neutralizing anti-HIV-1 monoclonal antibodies in the clinic. Nat. Med. 25, 547–553 (2019).
pubmed: 30936546
pmcid: 7322694
doi: 10.1038/s41591-019-0412-8
Julg, B. & Barouch, D. Broadly neutralizing antibodies for HIV-1 prevention and therapy. Semin. Immunol. 51, 101475 (2021).
pubmed: 33858765
doi: 10.1016/j.smim.2021.101475
Caskey, M. et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522, 487 (2015).
pubmed: 25855300
pmcid: 4890714
doi: 10.1038/nature14411
Lynch, R. M. et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci. Transl. Med. 7, 319ra206–319ra206 (2015).
pubmed: 26702094
doi: 10.1126/scitranslmed.aad5752
Caskey, M. et al. Antibody 10-1074 suppresses viremia in HIV-1-infected individuals. Nat. Med. 23, 185–191 (2017).
pubmed: 28092665
pmcid: 5467219
doi: 10.1038/nm.4268
Scheid, J. F. et al. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature 535, 556 (2016).
pubmed: 27338952
pmcid: 5034582
doi: 10.1038/nature18929
Mendoza, P. et al. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature 561, 479–484 (2018).
pubmed: 30258136
pmcid: 6166473
doi: 10.1038/s41586-018-0531-2
Bruel, T. et al. Elimination of HIV-1-infected cells by broadly neutralizing antibodies. Nat. Commun. 7, 10844 (2016).
pubmed: 26936020
pmcid: 4782064
doi: 10.1038/ncomms10844
von Bredow, B. et al. Envelope glycoprotein internalization protects human and simian immunodeficiency virus-infected cells from antibody-dependent cell-mediated cytotoxicity. J. Virol. 89, 10648–10655 (2015).
pubmed: 26269175
pmcid: 4580155
doi: 10.1128/JVI.01911-15
Veillette, M. et al. Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity. J. Virol. 88, 2633–2644 (2014).
pubmed: 24352444
pmcid: 3958102
doi: 10.1128/JVI.03230-13
Musich, T. et al. Monoclonal antibodies specific for the V2, V3, CD4-binding site, and gp41 of HIV-1 mediate phagocytosis in a dose-dependent manner. J. Virol. 91, e02325–16 (2017).
pubmed: 28122974
pmcid: 5375680
doi: 10.1128/JVI.02325-16
Dufloo, J. et al. Anti‐HIV‐1 antibodies trigger non‐lytic complement deposition on infected cells. Embo Rep. 21, e49351 (2019).
pubmed: 31833228
Hessell, A. J. et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449, 101–104 (2007).
pubmed: 17805298
doi: 10.1038/nature06106
Bournazos, S. et al. Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell 158, 1243–1253 (2014).
pubmed: 25215485
pmcid: 4167398
doi: 10.1016/j.cell.2014.08.023
Parsons, M. S. et al. Fc-dependent functions are redundant to efficacy of anti-HIV antibody PGT121 in macaques. J. Clin. Invest. 129, 182–191 (2018).
pubmed: 30475230
pmcid: 6307963
doi: 10.1172/JCI122466
Hangartner, L. et al. Effector function does not contribute to protection from virus challenge by a highly potent HIV broadly neutralizing antibody in nonhuman primates. Sci. Transl. Med. 13, eabe3349 (2021).
pubmed: 33731434
pmcid: 8049513
doi: 10.1126/scitranslmed.abe3349
Asokan, M. et al. Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody. Proc. Natl Acad. Sci. USA 117, 18754–18763 (2020).
pubmed: 32690707
pmcid: 7414046
doi: 10.1073/pnas.2008236117
Jin, J. et al. Neutralizing antibodies inhibit chikungunya virus budding at the plasma membrane. Cell Host Microbe 24, 417–428.e5 (2018).
pubmed: 30146390
pmcid: 6137268
doi: 10.1016/j.chom.2018.07.018
Jin, J. et al. Neutralizing monoclonal antibodies block chikungunya virus entry and release by targeting an epitope critical to viral pathogenesis. Cell Rep. 13, 2553–2564 (2015).
pubmed: 26686638
pmcid: 4720387
doi: 10.1016/j.celrep.2015.11.043
Bangaru, S. et al. A multifunctional human monoclonal neutralizing antibody that targets a unique conserved epitope on influenza HA. Nat. Commun. 9, 2669 (2018).
pubmed: 29991715
pmcid: 6039445
doi: 10.1038/s41467-018-04704-9
Teimoori, S. et al. Human transbodies to VP40 inhibit cellular egress of Ebola virus-like particles. Biochem. Bioph. Res. Co. 479, 245–252 (2016).
doi: 10.1016/j.bbrc.2016.09.052
Kajihara, M. et al. Inhibition of marburg virus budding by nonneutralizing antibodies to the envelope glycoprotein. J. Virol. 86, 13467–13474 (2012).
pubmed: 23035224
pmcid: 3503067
doi: 10.1128/JVI.01896-12
Murphy, R. E. & Saad, J. S. The interplay between HIV-1 Gag binding to the plasma membrane and Env incorporation. Viruses 12, 548 (2020).
pmcid: 7291237
doi: 10.3390/v12050548
Freed, E. O. HIV-1 assembly, release and maturation. Nat. Rev. Microbiol. 13, 484–496 (2015).
pubmed: 26119571
pmcid: 6936268
doi: 10.1038/nrmicro3490
Lu, L. L., Suscovich, T. J., Fortune, S. M. & Alter, G. Beyond binding: antibody effector functions in infectious diseases. Nat. Rev. Immunol. 18, 46–61 (2018).
pubmed: 29063907
doi: 10.1038/nri.2017.106
Diebolder, C. A. et al. Complement is activated by IgG hexamers assembled at the cell. Science. 343, 1260–1263 (2014).
pubmed: 24626930
pmcid: 4250092
doi: 10.1126/science.1248943
Richard, J., Prévost, J., Alsahafi, N., Ding, S. & Finzi, A. Impact of HIV-1 envelope conformation on ADCC responses. Trends Microbiol. 26, 253–265 (2018).
pubmed: 29162391
doi: 10.1016/j.tim.2017.10.007
Bruel, T. et al. Lack of ADCC breadth of human nonneutralizing Anti-HIV-1 antibodies. J. Virol. 91, e02440–16 (2017).
pubmed: 28122982
pmcid: 5375671
doi: 10.1128/JVI.02440-16
von Bredow, B. et al. Comparison of antibody-dependent cell-mediated cytotoxicity and virus neutralization by HIV-1 Env-specific monoclonal antibodies. J. Virol. 90, 6127–6139 (2016).
pubmed: 27122574
pmcid: 4907221
doi: 10.1128/JVI.00347-16
Neil, S. J. D., Zang, T. & Bieniasz, P. D. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451, 425–430 (2008).
pubmed: 18200009
doi: 10.1038/nature06553
Damme, N. V. et al. The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral vpu protein. Cell Host Microbe 3, 245–252 (2008).
pubmed: 18342597
pmcid: 2474773
doi: 10.1016/j.chom.2008.03.001
Galão, R. P., Le Tortorec, A., Pickering, S., Kueck, T. & Neil, S. J. D. Innate sensing of HIV-1 assembly by tetherin induces NFκB-dependent proinflammatory responses. Cell Host Microbe 12, 633–644 (2012).
pubmed: 23159053
pmcid: 3556742
doi: 10.1016/j.chom.2012.10.007
Anand, S. P. et al. Antibody-induced internalization of HIV-1 Env proteins limits surface expression of the closed conformation of Env. J. Virol. 93, e00293-19 (2019).
Malbec, M. et al. Broadly neutralizing antibodies that inhibit HIV-1 cell to cell transmission. J. Exp. Med. 210, 2813–2821 (2013).
pubmed: 24277152
pmcid: 3865481
doi: 10.1084/jem.20131244
Jouvenet, N., Bieniasz, P. D. & Simon, S. M. Imaging the biogenesis of individual HIV-1 virions in live cells. Nature 454, 236–240 (2008).
pubmed: 18500329
pmcid: 2708942
doi: 10.1038/nature06998
Tan, J. & Sattentau, Q. J. The HIV-1-containing macrophage compartment: a perfect cellular niche? Trends Microbiol. 21, 405–412 (2013).
pubmed: 23735804
doi: 10.1016/j.tim.2013.05.001
Akiyama, H., Ramirez, N.-G. P., Gudheti, M. V. & Gummuluru, S. CD169-mediated trafficking of HIV to plasma membrane invaginations in dendritic cells attenuates efficacy of anti-gp120 broadly neutralizing antibodies. PLoS Pathog. 11, e1004751 (2015).
pubmed: 25760631
pmcid: 4356592
doi: 10.1371/journal.ppat.1004751
Koppensteiner, H., Banning, C., Schneider, C., Hohenberg, H. & Schindler, M. Macrophage internal HIV-1 is protected from neutralizing antibodies. J. Virol. 86, 2826–2836 (2012).
pubmed: 22205742
pmcid: 3302290
doi: 10.1128/JVI.05915-11
Nishimura, Y. et al. Early antibody therapy can induce long-lasting immunity to SHIV. Nature 543, 559–563 (2017).
pubmed: 28289286
pmcid: 5458531
doi: 10.1038/nature21435
Ng, C. T. et al. Passive neutralizing antibody controls SHIV viremia and enhances B cell responses in infant macaques. Nat. Med. 16, 1117–1119 (2010).
pubmed: 20890292
pmcid: 2952052
doi: 10.1038/nm.2233
Schoofs, T. et al. HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1. Science 352, 997–1001 (2016).
pubmed: 27199429
pmcid: 5151174
doi: 10.1126/science.aaf0972
Naranjo-Gomez, M. & Pelegrin, M. Vaccinal effect of HIV-1 antibody therapy. Curr. Opin. Hiv. Aids 14, 325–333 (2019).
pubmed: 30973419
doi: 10.1097/COH.0000000000000555
Stieh, D. J. et al. Aggregate complexes of HIV-1 induced by multimeric antibodies. Retrovirology 11, 78 (2014).
pubmed: 25274446
pmcid: 4193994
doi: 10.1186/s12977-014-0078-8
Alexander, M. R., Sanders, R. W., Moore, J. P. & Klasse, P. J. Short communication: virion aggregation by neutralizing and nonneutralizing antibodies to the HIV-1 envelope glycoprotein. Aids Res. Hum. Retrov. 31, 1160–1165 (2015).
doi: 10.1089/aid.2015.0050
Roy, N. H., Chan, J., Lambelé, M. & Thali, M. Clustering and mobility of HIV-1 Env at viral assembly sites predict its propensity to induce cell-cell fusion. J. Virol. 87, 7516–7525 (2013).
pubmed: 23637402
pmcid: 3700267
doi: 10.1128/JVI.00790-13
Lorin, V. & Mouquet, H. Efficient generation of human IgA monoclonal antibodies. J. Immunol. Methods 422, 102–110 (2015).
pubmed: 25910833
doi: 10.1016/j.jim.2015.04.010
Kumar, A., Planchais, C., Fronzes, R., Mouquet, H. & Reyes, N. Binding mechanisms of therapeutic antibodies to human CD20. Science 369, 793–799 (2020).
pubmed: 32792392
doi: 10.1126/science.abb8008
Sluis, R. M. V.d. et al. Diverse effects of interferon alpha on the establishment and reversal of HIV latency. PLoS Pathog. 16, e1008151 (2020).
pubmed: 32109259
pmcid: 7065813
doi: 10.1371/journal.ppat.1008151
Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).
pubmed: 12920303
doi: 10.1126/science.1086907
Scheid, J. F. et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 333, 1633–1637 (2011).
pubmed: 21764753
pmcid: 3351836
doi: 10.1126/science.1207227
Huang, J. et al. Identification of a CD4-binding-site antibody to HIV that evolved near-pan neutralization breadth. Immunity 45, 1108–1121 (2016).
pubmed: 27851912
pmcid: 5770152
doi: 10.1016/j.immuni.2016.10.027
Wu, X. et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329, 856–861 (2010).
pubmed: 20616233
pmcid: 2965066
doi: 10.1126/science.1187659
Liao, H.-X. et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496, 469–476 (2013).
pubmed: 23552890
pmcid: 3637846
doi: 10.1038/nature12053
Mouquet, H. et al. Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. Proc. Natl Acad. Sci. USA 109, E3268–E3277 (2012).
pubmed: 23115339
pmcid: 3511153
doi: 10.1073/pnas.1217207109
Walker, L. M. et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477, 466–470 (2011).
pubmed: 21849977
pmcid: 3393110
doi: 10.1038/nature10373
Sok, D. et al. Recombinant HIV envelope trimer selects for quaternary-dependent antibodies targeting the trimer apex. Proc. Natl Acad. Sci. USA 111, 17624–17629 (2014).
pubmed: 25422458
pmcid: 4267403
doi: 10.1073/pnas.1415789111
Walker, L. M. et al. Broad and potent neutralizing antibodies from an african donor reveal a new HIV-1 vaccine target. Science 326, 285–289 (2009).
pubmed: 19729618
pmcid: 3335270
doi: 10.1126/science.1178746
Zhu, Z. et al. Cross-reactive HIV-1-neutralizing human monoclonal antibodies identified from a patient with 2F5-Like antibodies. J. Virol. 85, 11401–11408 (2011).
pubmed: 21880764
pmcid: 3194990
doi: 10.1128/JVI.05312-11
Huang, J. et al. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491, 406–412 (2012).
pubmed: 23151583
pmcid: 4854285
doi: 10.1038/nature11544
Buchacher, A. et al. Generation of human monoclonal antibodies against HIV-1 proteins; electrofusion and epstein-barr virus transformation for peripheral blood lymphocyte immortalization. Aids Res. Hum. Retrov. 10, 359–369 (1994).
doi: 10.1089/aid.1994.10.359
Klein, F. et al. Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein. J. Exp. Med. 209, 1469–1479 (2012).
pubmed: 22826297
pmcid: 3409500
doi: 10.1084/jem.20120423
Scheid, J. F. et al. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 458, 636–640 (2009).
pubmed: 19287373
doi: 10.1038/nature07930