Broadly neutralizing anti-HIV-1 antibodies tether viral particles at the surface of infected cells.


Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
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

630

Informations 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

Auteurs

Jérémy Dufloo (J)

Institut Pasteur, Université de Paris, CNRS UMR3569, Virus and Immunity Unit, 75015, Paris, France.
Université de Paris, École doctorale BioSPC 562, 75013, Paris, France.
Institute for Integrative Systems Biology (I2SysBio), Universitat de València-CSIC, 46980, València, Spain.

Cyril Planchais (C)

Institut Pasteur, Université de Paris, INSERM U1222, Humoral Immunology Laboratory, 75015, Paris, France.

Stéphane Frémont (S)

Institut Pasteur, Université de Paris, CNRS UMR3691, Membrane Traffic and Cell Division Unit, 75015, Paris, France.

Valérie Lorin (V)

Institut Pasteur, Université de Paris, INSERM U1222, Humoral Immunology Laboratory, 75015, Paris, France.

Florence Guivel-Benhassine (F)

Institut Pasteur, Université de Paris, CNRS UMR3569, Virus and Immunity Unit, 75015, Paris, France.

Karl Stefic (K)

CHRU de Tours, Hôpital Bretonneau, Service de Bactériologie-Virologie, 37000, Tours, France.

Nicoletta Casartelli (N)

Institut Pasteur, Université de Paris, CNRS UMR3569, Virus and Immunity Unit, 75015, Paris, France.

Arnaud Echard (A)

Institut Pasteur, Université de Paris, CNRS UMR3691, Membrane Traffic and Cell Division Unit, 75015, Paris, France.

Philippe Roingeard (P)

Université de Tours, CHRU de Tours, INSERM U1259 MAVIVH and Plateforme IBiSA de Microscopie Électronique, 37000, Tours, France.

Hugo Mouquet (H)

Institut Pasteur, Université de Paris, INSERM U1222, Humoral Immunology Laboratory, 75015, Paris, France.

Olivier Schwartz (O)

Institut Pasteur, Université de Paris, CNRS UMR3569, Virus and Immunity Unit, 75015, Paris, France. olivier.schwartz@pasteur.fr.
Vaccine Research Institute, 94000, Créteil, France. olivier.schwartz@pasteur.fr.

Timothée Bruel (T)

Institut Pasteur, Université de Paris, CNRS UMR3569, Virus and Immunity Unit, 75015, Paris, France. timothee.bruel@pasteur.fr.
Vaccine Research Institute, 94000, Créteil, France. timothee.bruel@pasteur.fr.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female
Humans United States Aged Cross-Sectional Studies Medicare Part C
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH