Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody

Mangaiarkarasi Asokan; Joana Diasb; Cuiping Liu; Anna Maximovaa; Keenan Ernste; Amarendra Pegu; Krisha McKee; Wei Shi; Xuejun Chen; Cassandra Almasri; Wanwisa Promsote; David R. Ambrozak; Lucio Gama; Jianfei Hu; Daniel C. Douek; John Paul Todd; Jeffrey D. Lifson; Slim Fourati; Rafick P. Sekaly; Andrew R. Crowley; Margaret E. Ackerman; Sung Hee Ko; Divya Kilam; Eli A. Boritz; Laura E. Liao; Katharine Best; Alan S. Perelson; John R. Mascola; Richard A. Koup

doi:10.1073/pnas.2008236117

Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody

Mangaiarkarasi Asokan, Joana Diasb, Cuiping Liu, Anna Maximovaa, Keenan Ernste, Amarendra Pegu, Krisha McKee, Wei Shi, Xuejun Chen, Cassandra Almasri, Wanwisa Promsote, David R. Ambrozak, Lucio Gama, Jianfei Hu, Daniel C. Douek, John Paul Todd, Jeffrey D. Lifson, Slim Fourati, Rafick P. Sekaly, Andrew R. CrowleyMargaret E. Ackerman, Sung Hee Ko, Divya Kilam, Eli A. Boritz, Laura E. Liao, Katharine Best, Alan S. Perelson, John R. Mascola, Richard A. Koup

School of Medicine

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Treatment of HIV infection with either antiretroviral (ARV) therapy or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ARVs and NAbs prevent new rounds of viral infection, but NAbs may have the additional capacity to accelerate the loss of virus-infected cells through Fc gamma receptor (FcγR)-mediated effector functions, which should affect the kinetics of plasma-virus decline. Here, we formally test the role of effector function in vivo by comparing the rate and timing of plasma-virus clearance in response to a single-dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic simian HIV (SHIV)-infected rhesus macaques, there was a 21% difference in slope of plasma-virus decline between NAb and NAb with reduced Fc function. NAb engineered to increase FcγRIII binding and improve antibody-dependent cellular cytotoxicity (ADCC) in vitro resulted in arming of effector cells in vivo, yet led to viral-decay kinetics similar to NAbs with reduced Fc function. These studies show that the predominantmechanism of antiviral activity of HIV NAbs is through inhibition of viral entry, but that Fc function can contribute to the overall antiviral activity, making them distinct from standard ARVs.

Original language	English (US)
Pages (from-to)	18754-18763
Number of pages	10
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Issue number	31
DOIs	https://doi.org/10.1073/pnas.2008236117
State	Published - Aug 4 2020

Keywords

Effector function
Fc
HIV
Mechanism of action
Neutralizing antibodies

ASJC Scopus subject areas

General

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10.1073/pnas.2008236117

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Asokan, M., Diasb, J., Liu, C., Maximovaa, A., Ernste, K., Pegu, A., McKee, K., Shi, W., Chen, X., Almasri, C., Promsote, W., Ambrozak, D. R., Gama, L., Hu, J., Douek, D. C., Todd, J. P., Lifson, J. D., Fourati, S., Sekaly, R. P., ... Koup, R. A. (2020). Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody. Proceedings of the National Academy of Sciences of the United States of America, 117(31), 18754-18763. https://doi.org/10.1073/pnas.2008236117

Asokan, M, Diasb, J, Liu, C, Maximovaa, A, Ernste, K, Pegu, A, McKee, K, Shi, W, Chen, X, Almasri, C, Promsote, W, Ambrozak, DR, Gama, L, Hu, J, Douek, DC, Todd, JP, Lifson, JD, Fourati, S, Sekaly, RP, Crowley, AR, Ackerman, ME, Ko, SH, Kilam, D, Boritz, EA, Liao, LE, Best, K, Perelson, AS, Mascola, JR & Koup, RA 2020, 'Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 31, pp. 18754-18763. https://doi.org/10.1073/pnas.2008236117

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abstract = "Treatment of HIV infection with either antiretroviral (ARV) therapy or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ARVs and NAbs prevent new rounds of viral infection, but NAbs may have the additional capacity to accelerate the loss of virus-infected cells through Fc gamma receptor (FcγR)-mediated effector functions, which should affect the kinetics of plasma-virus decline. Here, we formally test the role of effector function in vivo by comparing the rate and timing of plasma-virus clearance in response to a single-dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic simian HIV (SHIV)-infected rhesus macaques, there was a 21% difference in slope of plasma-virus decline between NAb and NAb with reduced Fc function. NAb engineered to increase FcγRIII binding and improve antibody-dependent cellular cytotoxicity (ADCC) in vitro resulted in arming of effector cells in vivo, yet led to viral-decay kinetics similar to NAbs with reduced Fc function. These studies show that the predominantmechanism of antiviral activity of HIV NAbs is through inhibition of viral entry, but that Fc function can contribute to the overall antiviral activity, making them distinct from standard ARVs.",

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AU - Asokan, Mangaiarkarasi

AU - Diasb, Joana

AU - Liu, Cuiping

AU - Maximovaa, Anna

AU - Ernste, Keenan

AU - Pegu, Amarendra

AU - McKee, Krisha

AU - Shi, Wei

AU - Chen, Xuejun

AU - Almasri, Cassandra

AU - Promsote, Wanwisa

AU - Ambrozak, David R.

AU - Gama, Lucio

AU - Hu, Jianfei

AU - Douek, Daniel C.

AU - Todd, John Paul

AU - Lifson, Jeffrey D.

AU - Fourati, Slim

AU - Sekaly, Rafick P.

AU - Crowley, Andrew R.

AU - Ackerman, Margaret E.

AU - Ko, Sung Hee

AU - Kilam, Divya

AU - Boritz, Eli A.

AU - Liao, Laura E.

AU - Best, Katharine

AU - Perelson, Alan S.

AU - Mascola, John R.

AU - Koup, Richard A.

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N2 - Treatment of HIV infection with either antiretroviral (ARV) therapy or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ARVs and NAbs prevent new rounds of viral infection, but NAbs may have the additional capacity to accelerate the loss of virus-infected cells through Fc gamma receptor (FcγR)-mediated effector functions, which should affect the kinetics of plasma-virus decline. Here, we formally test the role of effector function in vivo by comparing the rate and timing of plasma-virus clearance in response to a single-dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic simian HIV (SHIV)-infected rhesus macaques, there was a 21% difference in slope of plasma-virus decline between NAb and NAb with reduced Fc function. NAb engineered to increase FcγRIII binding and improve antibody-dependent cellular cytotoxicity (ADCC) in vitro resulted in arming of effector cells in vivo, yet led to viral-decay kinetics similar to NAbs with reduced Fc function. These studies show that the predominantmechanism of antiviral activity of HIV NAbs is through inhibition of viral entry, but that Fc function can contribute to the overall antiviral activity, making them distinct from standard ARVs.

AB - Treatment of HIV infection with either antiretroviral (ARV) therapy or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ARVs and NAbs prevent new rounds of viral infection, but NAbs may have the additional capacity to accelerate the loss of virus-infected cells through Fc gamma receptor (FcγR)-mediated effector functions, which should affect the kinetics of plasma-virus decline. Here, we formally test the role of effector function in vivo by comparing the rate and timing of plasma-virus clearance in response to a single-dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic simian HIV (SHIV)-infected rhesus macaques, there was a 21% difference in slope of plasma-virus decline between NAb and NAb with reduced Fc function. NAb engineered to increase FcγRIII binding and improve antibody-dependent cellular cytotoxicity (ADCC) in vitro resulted in arming of effector cells in vivo, yet led to viral-decay kinetics similar to NAbs with reduced Fc function. These studies show that the predominantmechanism of antiviral activity of HIV NAbs is through inhibition of viral entry, but that Fc function can contribute to the overall antiviral activity, making them distinct from standard ARVs.

KW - Effector function

KW - Fc

KW - HIV

KW - Mechanism of action

KW - Neutralizing antibodies

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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ER -

Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody

Abstract

Keywords

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