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This appears due to HCMV\u2019s multiple immune evasion mechanisms, including viral receptors (vFc\u03b3Rs) which bind human IgG Fc domains to co-operatively inhibit Fc activation of host Fc\u03b3 receptors and impair Fc-mediated effector functions. We biochemically characterized and evaluated the functions of two highly conserved vFc\u03b3Rs, gp34 and gp68, and mapped their binding epitopes on the Fc domain. Based on this information, we then engineered Fc variants that retain binding to CD16A, which is essential for NK activation, and to FcRn but have markedly attenuated binding to gp34 and gp68. IgG1 antibodies targeting the gB fusogen with engineered Fc domains were not internalized by infected cells, mediated enhanced CD16A activation and limited viral spread in HCMV-infected fibroblasts more effectively than wild-type Fc. Together, this work demonstrates a strategy to enhance the efficacy of antibody therapies to clear HCMV infections.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Host and HCMV FcR compete for IgG1 binding but engage different residues.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Fc-engineering abrogates viral FcR antagonism while retaining CD16A activation.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Antibodies that resist vFcR capture promote superior ADCC against infected cells.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Designer Fc domains complement Fabs to create enhanced disease-specific therapies.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.04.12.647817","type":"posted-content","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T12:04:11Z","timestamp":1745409851000},"source":"Crossref","is-referenced-by-count":1,"title":["Selective decoupling of IgG1 binding to viral Fc receptors restores antibody-mediated NK cell activation against HCMV"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4694-5619","authenticated-orcid":false,"given":"Ahlam N.","family":"Qerqez","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, University of Texas, Austin, Texas 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3749-9047","authenticated-orcid":false,"given":"Katja","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Institute of Virology, University Medical 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