{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T19:29:25Z","timestamp":1763580565328,"version":"3.41.2"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T00:00:00Z","timestamp":1750982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Progressive multifocal leukoencephalopathy (PML), caused by John Cunningham (JC) virus reactivation, represents a critical neurological complication in AIDS-related immunosuppression. This single-center study conducted a clinicopathological analysis of 19 confirmed PML cases in an AIDS cohort (16 biopsy; 3 surgical specimens), employing comprehensive neuropathological evaluation. Immunohistochemical testing included SV40, NF, NeuN, P53, Ki-67, GFAP, Oligo-2, and CD68. Myelin architecture was evaluated through Luxol fast blue staining, complemented by molecular diagnostics incorporating quantitative JC viral load PCR and metagenomic next-generation sequencing (mNGS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Notably, 63.2% (12\/19) of them had blood CD4+ T-cell counts &amp;lt; 200 cells\/\u03bcl, and 36.8% (7\/19) had \u2265 200 cells\/\u03bcl. 52.9% (9\/17) of the patients had elevated CSF protein, 5.3% (1\/19) had decreased CSF glucose. Statistical analysis revealed significant correlations between mass effect and both blood CD4+ T-cell counts (<jats:italic>P<\/jats:italic> = 0.022) and CSF protein levels (<jats:italic>P<\/jats:italic> &amp;lt; 0.001). It also demonstrated significant positive correlations between the duration of HIV diagnosis and the degree of inflammatory infiltration (<jats:italic>P<\/jats:italic> = 0.038) and perivascular inflammatory infiltration (<jats:italic>P<\/jats:italic> = 0.005), as well as plasma cell infiltration (<jats:italic>P<\/jats:italic> = 0.011). The degree of inflammatory infiltration was significantly positively correlated with antiretroviral therapy (ART) (<jats:italic>P<\/jats:italic> = 0.036). The degree of inflammatory infiltration, the presence of plasma cells, and perivascular lymphocytic cuffing were significantly associated with contrast enhancement on imaging studies (<jats:italic>P<\/jats:italic> = 0.044, <jats:italic>P<\/jats:italic> = 0.011, and <jats:italic>P<\/jats:italic> = 0.018, respectively). These cases display characteristics that deviate from the classic PML previously reported, exhibiting a tendency towards MRI enhancement and histologically indicating a more severe inflammatory response, especially for patients following ART treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings suggest that PML and PML-immune reconstitution inflammatory syndrome (IRIS) represent a continuous pathological spectrum, potentially bridged by an intermediate stage with distinct clinicopathological features. This transitional phase may constitute a critical link in the continuum between classic PML and fully developed PML-IRIS. Importantly, it implicates synergistic mechanisms of viral oncogenesis and immune reconstitution, which could redefine therapeutic strategies for this emerging PML variant.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1607428","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T05:32:29Z","timestamp":1751002349000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The boundaries between PML and PML-IRIS: difficult to define, pathology may predict"],"prefix":"10.3389","volume":"15","author":[{"given":"Jiamin","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanni","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuyang","family":"Dai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinghuan","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyi","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Man","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1080\/13550280390195388","article-title":"Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA)","author":"Antinori","year":"2003","journal-title":"J. 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