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

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)18754-18763
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number31
DOIs
StatePublished - Aug 4 2020
Externally publishedYes

Keywords

  • Effector function
  • Fc
  • HIV
  • Mechanism of action
  • Neutralizing antibodies

ASJC Scopus subject areas

  • General

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