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

Author:

Asokan MangaiarkarasiORCID,Dias Joana,Liu Cuiping,Maximova Anna,Ernste KeenanORCID,Pegu AmarendraORCID,McKee Krisha,Shi Wei,Chen Xuejun,Almasri Cassandra,Promsote Wanwisa,Ambrozak David R.,Gama Lucio,Hu Jianfei,Douek Daniel C.,Todd John-Paul,Lifson Jeffrey D.,Fourati SlimORCID,Sekaly Rafick P.,Crowley Andrew R.,Ackerman Margaret E.ORCID,Ko Sung Hee,Kilam Divya,Boritz Eli A.,Liao Laura E.ORCID,Best Katharine,Perelson Alan S.ORCID,Mascola John R.,Koup Richard A.ORCID

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 predominant mechanism 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.

Funder

HHS | NIH | National Cancer Institute

U.S. Department of Energy

HHS | National Institutes of Health

Bill and Melinda Gates Foundation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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