@article{e5dd6c95a6624d72ab1d1eee72a6d221,
title = "The mechanistic basis of protection by non-neutralizing anti-alphavirus antibodies",
abstract = "Although neutralizing monoclonal antibodies (mAbs) against epitopes within the alphavirus E2 protein can protect against infection, the functional significance of non-neutralizing mAbs is poorly understood. Here, we evaluate the activity of 13 non-neutralizing mAbs against Mayaro virus (MAYV), an emerging arthritogenic alphavirus. These mAbs bind to the MAYV virion and surface of infected cells but fail to neutralize infection in cell culture. Mapping studies identify six mAb binding groups that localize to discrete epitopes within or adjacent to the A domain of the E2 glycoprotein. Remarkably, passive transfer of non-neutralizing mAbs protects against MAYV infection and disease in mice, and their efficacy requires Fc effector functions. Monocytes mediate the protection of non-neutralizing mAbs in vivo, as Fcγ-receptor-expressing myeloid cells facilitate the binding, uptake, and clearance of MAYV without antibody-dependent enhancement of infection. Humoral protection against alphaviruses likely reflects contributions from non-neutralizing antibodies through Fc-dependent mechanisms that accelerate viral clearance.",
keywords = "Fc effector, alphavirus, antibody, epitope, mapping, monocytes, neutralization, pathogenesis, protection",
author = "Earnest, {James T.} and Holmes, {Autumn C.} and Katherine Basore and Matthias Mack and Fremont, {Daved H.} and Diamond, {Michael S.}",
note = "Funding Information: This work was supported by NIH grants R01 AI141436, R01 AI114816, and U19 AI142790 and contracts AI201800001, 75N93019C00062, and HHSN272201700060C. We thank Michelle Noll for mouse husbandry and Ted Pierson for comments on the manuscript. BioRender software was used to generate some of the images. Conceptualization: J.T.E. A.C.H. K.B. D.H.F. and M.S.D.; methodology and resources: J.T.E. A.C.H. K.B. M.M. D.H.F. and M.S.D.; investigation: J.T.E. A.C.H. and K.B.; writing, original draft: J.T.E. K.B. and M.S.D.; writing, review and editing: J.T.E. A.C.H. K.B. M.M. D.H.F. and M.S.D.; funding acquisition: D.H.F. and M.S.D. M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and the Carnival Corporation and on the Scientific Advisory Board of Moderna and Immunome. The Diamond laboratory has received sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. Funding Information: This work was supported by NIH grants R01 AI141436 , R01 AI114816 , and U19 AI142790 and contracts AI201800001 , 75N93019C00062 , and HHSN272201700060C . We thank Michelle Noll for mouse husbandry and Ted Pierson for comments on the manuscript. BioRender software was used to generate some of the images. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = apr,
day = "6",
doi = "10.1016/j.celrep.2021.108962",
language = "English",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
number = "1",
}