Quantifying the contribution of Fc-mediated effector functions to the antiviral activity of anti–HIV-1 IgG1 antibodies in vivo

Wang, Pengfei; Gajjar, Mili R.; Yu, Jian; Padte, Neal N.; Gettie, Agegnehu; Blanchard, James L.; Russell-Lodrigue, Kasi; Liao, Laura E.; Perelson, Alan S.; Huang, Yaoxing; Ho, David D.

doi:10.1073/pnas.2008190117

Quantifying the contribution of Fc-mediated effector functions to the antiviral activity of anti–HIV-1 IgG1 antibodies in vivo

Journal Article · Tue Jul 14 00:00:00 EDT 2020 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2008190117· OSTI ID:1764197

^[1]; Gajjar, Mili R. ^[1]; Yu, Jian ^[1]; Padte, Neal N. ^[1]; Gettie, Agegnehu ^[1]; Blanchard, James L. ^[2]; ^[2]; ^[3]; ^[3]; Huang, Yaoxing ^[1]; Ho, David D. ^[1]

Columbia Univ., New York, NY (United States)
Tulane Univ., New Orleans, LA (United States)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

In combating viral infections, the Fab portion of an antibody could mediate virus neutralization, whereas Fc engagement of Fc-γ receptors (FcγRs) could mediate an array of effector functions. Evidence abounds that effector functions are important in controlling infections by influenza, Ebola, or HIV-1 in animal models. However, the relative contribution of virus neutralization versus effector functions to the overall antiviral activity of an antibody remains unknown. To address this fundamental question in immunology, here we utilized our knowledge of HIV-1 dynamics to compare the kinetics of the viral load decline (ΔVL) in infected animals given a wild-type (WT) anti–HIV-1 immunoglobulin G1 (IgG1) versus those given a Fc-Null variant of the same antibody. In three independent experiments in HIV-1–infected humanized mice and one pivotal experiment in simian–human immunodeficiency virus (SHIV)-infected rhesus macaques, an earlier and sharper decline in viral load was consistently detected for the WT antibody. Quantifications of the observed differences indicate that Fc-mediated effector functions accounted for 25–45% of the total antiviral activity in these separate experiments. In this study, Fc-mediated effector functions have been quantified in vivo relative to the contribution of virus neutralization mediated by the Fab.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: Bill & Melinda Gates Foundation; National Institutes of Health (NIH); USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 1764197

Report Number(s):: LA-UR--19-28390

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 30 Vol. 117; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

References (50)

IgG Fc engineering to modulate antibody effector functions Wang, Xinhua; Mathieu, Mary; Brezski, Randall J. Protein & Cell, Vol. 9, Issue 1 https://doi.org/10.1007/s13238-017-0473-8	journal	October 2017
Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis Ramratnam, Bharat; Bonhoeffer, Sebastian; Binley, James The Lancet, Vol. 354, Issue 9192 https://doi.org/10.1016/S0140-6736(99)02035-8	journal	November 1999
Broadly Neutralizing Antibodies and Viral Inducers Decrease Rebound from HIV-1 Latent Reservoirs in Humanized Mice Halper-Stromberg, Ariel; Lu, Ching-Lan; Klein, Florian Cell, Vol. 158, Issue 5 https://doi.org/10.1016/j.cell.2014.07.043	journal	August 2014
Broadly Neutralizing Anti-HIV-1 Antibodies Require Fc Effector Functions for In Vivo Activity Bournazos, Stylianos; Klein, Florian; Pietzsch, John Cell, Vol. 158, Issue 6 https://doi.org/10.1016/j.cell.2014.08.023	journal	September 2014
Differential Fc-Receptor Engagement Drives an Anti-tumor Vaccinal Effect DiLillo, David J.; Ravetch, Jeffrey V. Cell, Vol. 161, Issue 5 https://doi.org/10.1016/j.cell.2015.04.016	journal	May 2015
Engineered Bispecific Antibodies with Exquisite HIV-1-Neutralizing Activity Huang, Yaoxing; Yu, Jian; Lanzi, Anastasia Cell, Vol. 165, Issue 7 https://doi.org/10.1016/j.cell.2016.05.024	journal	June 2016
Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection Saphire, Erica Ollmann; Schendel, Sharon L.; Fusco, Marnie L. Cell, Vol. 174, Issue 4 https://doi.org/10.1016/j.cell.2018.07.033	journal	August 2018
A Role for Fc Function in Therapeutic Monoclonal Antibody-Mediated Protection against Ebola Virus Gunn, Bronwyn M.; Yu, Wen-Han; Karim, Marcus M. Cell Host & Microbe, Vol. 24, Issue 2 https://doi.org/10.1016/j.chom.2018.07.009	journal	August 2018
Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth Huang, Jinghe; Kang, Byong H.; Ishida, Elise Immunity, Vol. 45, Issue 5 https://doi.org/10.1016/j.immuni.2016.10.027	journal	November 2016
Highly reduced binding to high and low affinity mouse Fc gamma receptors by L234A/L235A and N297A Fc mutations engineered into mouse IgG2a Arduin, E.; Arora, S.; Bamert, P. R. Molecular Immunology, Vol. 63, Issue 2 https://doi.org/10.1016/j.molimm.2014.09.017	journal	February 2015
Viral dynamics in human immunodeficiency virus type 1 infection Wei, Xiping; Ghosh, Sajal K.; Taylor, Maria E. Nature, Vol. 373, Issue 6510 https://doi.org/10.1038/373117a0	journal	January 1995
Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection Ho, David D.; Neumann, Avidan U.; Perelson, Alan S. Nature, Vol. 373, Issue 6510 https://doi.org/10.1038/373123a0	journal	January 1995
Decay characteristics of HIV-1-infected compartments during combination therapy Perelson, Alan S.; Essunger, Paulina; Cao, Yunzhen Nature, Vol. 387, Issue 6629 https://doi.org/10.1038/387188a0	journal	May 1997
Fc receptor but not complement binding is important in antibody protection against HIV Hessell, Ann J.; Hangartner, Lars; Hunter, Meredith Nature, Vol. 449, Issue 7158 https://doi.org/10.1038/nature06106	journal	September 2007
HIV therapy by a combination of broadly neutralizing antibodies in humanized mice Klein, Florian; Halper-Stromberg, Ariel; Horwitz, Joshua A. Nature, Vol. 492, Issue 7427 https://doi.org/10.1038/nature11604	journal	October 2012
Broadly neutralizing hemagglutinin stalk–specific antibodies require FcγR interactions for protection against influenza virus in vivo DiLillo, David J.; Tan, Gene S.; Palese, Peter Nature Medicine, Vol. 20, Issue 2 https://doi.org/10.1038/nm.3443	journal	January 2014
Beyond binding: antibody effector functions in infectious diseases Lu, Lenette L.; Suscovich, Todd J.; Fortune, Sarah M. Nature Reviews Immunology, Vol. 18, Issue 1 https://doi.org/10.1038/nri.2017.106	journal	October 2017
Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy Trial Haynes, Barton F.; Gilbert, Peter B.; McElrath, M. Juliana New England Journal of Medicine, Vol. 366, Issue 14 https://doi.org/10.1056/NEJMoa1113425	journal	April 2012
Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 envelope blocks binding and effector function of IgG Tomaras, G. D.; Ferrari, G.; Shen, X. Proceedings of the National Academy of Sciences, Vol. 110, Issue 22 https://doi.org/10.1073/pnas.1301456110	journal	May 2013
Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1 Pace, C. S.; Song, R.; Ochsenbauer, C. Proceedings of the National Academy of Sciences, Vol. 110, Issue 33 https://doi.org/10.1073/pnas.1304985110	journal	July 2013
Recombinant HIV envelope trimer selects for quaternary-dependent antibodies targeting the trimer apex Sok, Devin; van Gils, Marit J.; Pauthner, Matthias Proceedings of the National Academy of Sciences, Vol. 111, Issue 49 https://doi.org/10.1073/pnas.1415789111	journal	November 2014
Envelope residue 375 substitutions in simian–human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques Li, Hui; Wang, Shuyi; Kong, Rui Proceedings of the National Academy of Sciences, Vol. 113, Issue 24 https://doi.org/10.1073/pnas.1606636113	journal	May 2016
A large array of human monoclonal antibodies to type 1 human immunodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals. Burton, D. R.; Barbas, C. F.; Persson, M. A. Proceedings of the National Academy of Sciences, Vol. 88, Issue 22 https://doi.org/10.1073/pnas.88.22.10134	journal	November 1991
IgG Fc variant cross-reactivity between human and rhesus macaque FcγRs Boesch, Austin W.; Miles, Adam R.; Chan, Ying N. mAbs, Vol. 9, Issue 3 https://doi.org/10.1080/19420862.2016.1274845	journal	January 2017
Heterogeneous neutralizing antibody and antibody-dependent cell cytotoxicity responses in HIV-1 elite controllers Lambotte, Olivier; Ferrari, Guido; Moog, Christiane AIDS, Vol. 23, Issue 8 https://doi.org/10.1097/QAD.0b013e328329f97d	journal	January 2009
Activation of NK Cells by ADCC Antibodies and HIV Disease Progression Chung, Amy W.; Navis, Marjon; Isitman, Gamze JAIDS Journal of Acquired Immune Deficiency Syndromes, Vol. 58, Issue 2 https://doi.org/10.1097/QAI.0b013e31822c62b9	journal	January 2011
Structural characterization of a human Fc fragment engineered for lack of effector functions Oganesyan, Vaheh; Gao, Changshou; Shirinian, Lena Acta Crystallographica Section D Biological Crystallography, Vol. 64, Issue 6 https://doi.org/10.1107/S0907444908007877	journal	May 2008
Specific antibody-dependent cellular cytotoxicity responses associated with slow progression of HIV infection Wren, Leia H.; Chung, Amy W.; Isitman, Gamze Immunology, Vol. 138, Issue 2 https://doi.org/10.1111/imm.12016	journal	January 2013
The high-affinity receptor for IgG, FcγRI, of humans and non-human primates Chenoweth, Alicia M.; Trist, Halina M.; Tan, Peck-Szee Immunological Reviews, Vol. 268, Issue 1 https://doi.org/10.1111/imr.12366	journal	October 2015
Anti-retroviral antibody FcγR-mediated effector functions Bournazos, Stylianos; Ravetch, Jeffrey V. Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12482	journal	January 2017
Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding Scheid, J. F.; Mouquet, H.; Ueberheide, B. Science, Vol. 333, Issue 6049 https://doi.org/10.1126/science.1207227	journal	July 2011
Long-Acting Integrase Inhibitor Protects Macaques from Intrarectal Simian/Human Immunodeficiency Virus Andrews, C. D.; Spreen, W. R.; Mohri, H. Science, Vol. 343, Issue 6175 https://doi.org/10.1126/science.1248707	journal	March 2014
HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time Perelson, A. S.; Neumann, A. U.; Markowitz, M. Science, Vol. 271, Issue 5255 https://doi.org/10.1126/science.271.5255.1582	journal	March 1996
Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody Burton, D.; Pyati, J.; Koduri, R. Science, Vol. 266, Issue 5187 https://doi.org/10.1126/science.7973652	journal	November 1994
Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo Lu, C. -L.; Murakowski, D. K.; Bournazos, S. Science, Vol. 352, Issue 6288 https://doi.org/10.1126/science.aaf1279	journal	May 2016
Enhanced Antiretroviral Therapy in Rhesus Macaques Improves RT-SHIV Viral Decay Kinetics North, Thomas W.; Villalobos, Andradi; Hurwitz, Selwyn J. Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 7 https://doi.org/10.1128/AAC.02522-14	journal	April 2014
Rapid Viral Decay in Simian Immunodeficiency Virus-Infected Macaques Receiving Quadruple Antiretroviral Therapy Brandin, E.; Thorstensson, R.; Bonhoeffer, S. Journal of Virology, Vol. 80, Issue 19 https://doi.org/10.1128/JVI.00394-06	journal	September 2006
Tiered Categorization of a Diverse Panel of HIV-1 Env Pseudoviruses for Assessment of Neutralizing Antibodies Seaman, M. S.; Janes, H.; Hawkins, N. Journal of Virology, Vol. 84, Issue 3 https://doi.org/10.1128/JVI.02108-09	journal	November 2009
A Panel of IgG1 b12 Variants with Selectively Diminished or Enhanced Affinity for Fc Receptors To Define the Role of Effector Functions in Protection against HIV Moldt, B.; Schultz, N.; Dunlop, D. C. Journal of Virology, Vol. 85, Issue 20 https://doi.org/10.1128/JVI.05541-11	journal	August 2011
Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection. Nowak, M. A.; Lloyd, A. L.; Vasquez, G. M. Journal of virology, Vol. 71, Issue 10 https://doi.org/10.1128/JVI.71.10.7518-7525.1997	journal	January 1997
Antibody Protects Macaques against Vaginal Challenge with a Pathogenic R5 Simian/Human Immunodeficiency Virus at Serum Levels Giving Complete Neutralization In Vitro Parren, P. W. H. I.; Marx, P. A.; Hessell, A. J. Journal of Virology, Vol. 75, Issue 17 https://doi.org/10.1128/JVI.75.17.8340-8347.2001	journal	September 2001
A Novel Antiviral Intervention Results in More Accurate Assessment of Human Immunodeficiency Virus Type 1 Replication Dynamics and T-Cell Decay In Vivo Markowitz, M.; Louie, M.; Hurley, A. Journal of Virology, Vol. 77, Issue 8 https://doi.org/10.1128/JVI.77.8.5037-5038.2003	journal	April 2003
Fc-dependent functions are redundant to efficacy of anti-HIV antibody PGT121 in macaques Parsons, Matthew S.; Lee, Wen Shi; Kristensen, Anne B. Journal of Clinical Investigation, Vol. 129, Issue 1 https://doi.org/10.1172/JCI122466	journal	November 2018
Human NK cell development in NOD/SCID mice receiving grafts of cord blood CD34+ cells Kalberer, Christian P.; Siegler, Uwe; Wodnar-Filipowicz, Aleksandra Blood, Vol. 102, Issue 1 https://doi.org/10.1182/blood-2002-07-2024	journal	July 2003
Human NK cells of mice with reconstituted human immune system components require preactivation to acquire functional competence Strowig, Till; Chijioke, Obinna; Carrega, Paolo Blood, Vol. 116, Issue 20 https://doi.org/10.1182/blood-2010-02-270678	journal	November 2010
Engineering multi-specific antibodies against HIV-1 Padte, Neal N.; Yu, Jian; Huang, Yaoxing Retrovirology, Vol. 15, Issue 1 https://doi.org/10.1186/s12977-018-0439-9	journal	August 2018
Targeted Cytotoxic Therapy Kills Persisting HIV Infected Cells During ART Denton, Paul W.; Long, Julie M.; Wietgrefe, Stephen W. PLoS Pathogens, Vol. 10, Issue 1 https://doi.org/10.1371/journal.ppat.1003872	journal	January 2014
HIV-Specific Antibody Immunity Mediated Through NK Cells and Monocytes Kramski, Marit; Parsons, Matthew; Stratov, Ivan Current HIV Research, Vol. 11, Issue 5 https://doi.org/10.2174/1570162X113116660061	journal	November 2013
NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy Wang, Wei Frontiers in Immunology, Vol. 6 https://doi.org/10.3389/fimmu.2015.00368	journal	January 2015
Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics Stein, Christoph; Schubert, Ingo; Fey, Georg H. Antibodies, Vol. 1, Issue 1 https://doi.org/10.3390/antib1010088	journal	June 2012

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in vivo quantification
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Quantifying the contribution of Fc-mediated effector functions to the antiviral activity of anti–HIV-1 IgG1 antibodies in vivo

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