biostudies-literatureCramer PDeutsche Forschungsgemeinschaft (DFG)University of Rijekacroatian science foundation795-823https://www.ebi.ac.uk/biostudies/studies/S-EPMC12905349biostudies-literatureUnknown18(2)Virus infections elicit long-term IgG antibody and memory responses. Human cytomegalovirus (HCMV) is widespread in humans and disseminates despite the presence of virus-specific antibodies. Here, we report that the HCMV Fcγ-binding glycoprotein 34 modulates humoral immunity by binding to IgG⁺ memory B cells. gp34-B cell receptor (BCR) interaction initiates activation of the PDK1/AKT/mTOR/S6 pathway and BCR internalization in a SYK-independent manner. Prolonged stimulation also induces B-cell activation via upregulation of CD69 and CD86. In a T-cell-dependent response, however, interaction with gp34 blocks B-cell proliferation, differentiation into plasmablasts, and soluble IgG production, while stimulating TNF-α secretion. Through gp34 stimulation on IgG⁺ B cells, neighboring IgM⁺ and IgA⁺EMBO molecular medicineA viral glycoprotein targets IgG<sup>+</sup> memory B cells to mediate humoral immune evasion.PMC12905349SFP1160HE2526/9-2468499998KK.01.1.1.01.0006IP-2020-02-6617uniri-biomed-18-233JO1634/1-1Kolb PFalcone VRizzi MLenac Rovis TJanowska IJonjic SNeys SFHFiedler MKohl AKStaniek JPlachter BCramer PHuber MRead CHoffmann KHadlova PReinhard Hvon Einem JLorenzetti RHengel HfalseA viral glycoprotein targets IgG<sup>+</sup> memory B cells to mediate humoral immune evasion.Virus infections elicit long-term IgG antibody and memory responses. Human cytomegalovirus (HCMV) is widespread in humans and disseminates despite the presence of virus-specific antibodies. Here, we report that the HCMV Fcγ-binding glycoprotein 34 modulates humoral immunity by binding to IgG⁺ memory B cells. gp34-B cell receptor (BCR) interaction initiates activation of the PDK1/AKT/mTOR/S6 pathway and BCR internalization in a SYK-independent manner. Prolonged stimulation also induces B-cell activation via upregulation of CD69 and CD86. In a T-cell-dependent response, however, interaction with gp34 blocks B-cell proliferation, differentiation into plasmablasts, and soluble IgG production, while stimulating TNF-α secretion. Through gp34 stimulation on IgG⁺ B cells, neighboring IgM⁺ and IgA⁺2026-01-01T00:00:00Z2026 Feb2026-07-15T22:16:18.715Z2026-07-09T10:18:58.439ZS-EPMC129053494155937210.1038/s44321-026-00372-1