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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,7,14]]},"abstract":"<jats:p>The human JC polyomavirus (JCPyV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in immunocompromised individuals. JCPyV frequently undergoes mutations in PML patients, and these variants are thought to establish \u201cantibody recognition holes\u201d that enable the virus to circumvent the antibody response of infected individuals. Many of these PML-associated mutations cluster in the glycan receptor-binding site of the virus. Using X-ray crystallography, we investigated the binding modes of JCPyV VP1-specific human monoclonal antibodies (mAbs) that were isolated from healthy donors and individuals who recovered from PML, and that can recognize a panel of PML-associated JCPyV variants. Our structural analyses show that three out of four of these mAbs bind epitopes that overlap with the glycan\u2013receptor binding site at the surface of the virus particle. The observed interactions explain how PML-associated mutations strategically interfere with antibody recognition, resulting in immune evasion. In contrast, mAb 29B1 engages a region of the capsid that is distant from the glycan site and does not feature mutations associated with PML. The binding site is conserved in the closely related BK polyomavirus (BKPyV), and we show that mAb 29B1 binds both viruses with high affinity and blocks infection. Our findings form an excellent platform for the development of therapeutic Ab approaches and potential vaccination strategies that could protect at-risk patients from infections with both JCPyV and BKPyV. 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