{ "abstract": "Kaposi sarcoma (KS) exhibits profound clinical heterogeneity, yet current risk assessment remains constrained by anatomical staging systems that lack universality across diverse KS variants. This study characterized the functional impact of Kaposi’s sarcoma-associated herpesvirus (KSHV) K15 genotypes (M or P) on clinical aggressiveness in a retrospective cohort of 156 patients from Xinjiang, China. To enable unified analysis, we operationalized disease extent into a harmonized binary framework—categorized as localized or disseminated—by integrating anatomical criteria from the ACTG and Krigel classifications. Using causal mediation analysis to quantify the “Genotype–Inflammation–Edema” association, we identified the K15 M-genotype (72.8%) was independently associated with a hyper-inflammatory phenotype. This revealed a Viral–Clinical Paradox: despite significantly lower HIV coinfection rates compared to P-carriers (10.3% vs. 27.5%; P = 0.009), M-carriers exhibited an elevated Systemic Immune-Inflammation Index (SII) and severe clinical edema. Mediation analysis confirmed that the SII significantly mediated 29.0% (P = 0.009) of the genotype-associated effect on edema. To translate these biological insights into clinical utility, a six-factor prognostic nomogram was developed using LASSO regression, maintaining an events-per-variable ratio of 11.2. The model demonstrated robust discrimination (Concordance Index, 0.761) and significantly outperformed traditional anatomical observation (AUC, 0.830 vs. 0.563; P = 0.003). Risk stratification successfully identified distinct subgroups, separating patients with rapid progression (median progression-free survival: 11.0 months) from those with favorable outcomes (40.0 months; P < 0.0001). Our results suggest that the K15 M-genotype is associated with increased KS severity via intrinsic inflammatory activation, independent of host immunodeficiency. Integrating viral genotyping into clinical assessment may shift KS management from anatomical observation toward biology-driven precision oncology, identifying high-risk patients who may benefit from early systemic or anti-inflammatory interventions. Author summary: Kaposi sarcoma is a cancer caused by a viral infection. It affects patients in vastly different ways: some develop mild skin spots, while others suffer from rapidly growing tumors and swelling. Traditionally, doctors predict how a patient will fare by simply observing how far the tumors have physically spread. However, this visual method is often completely inaccurate. In our study, we asked whether small genetic differences in the virus itself could explain why some patients get much sicker than others. By analyzing 156 patients, we discovered that individuals infected with a specific genetic variant of the virus experienced a much more aggressive condition. We found that this specific viral variant is linked to severe, body-wide inflammation, which correlates with worse clinical outcomes, even in patients without underlying immune deficiencies. Using these biological insights, we developed a new risk-prediction tool that incorporates the genetics of the virus. We demonstrated that our biology-driven approach significantly outperforms traditional physical assessments. Our work suggests that routinely testing the virus’s genetics can help doctors precisely identify high-risk patients earlier, paving the way for targeted anti-inflammatory treatments to better manage this complex disease.", "abstract_shown": true, "affiliations": [ "Department of Dermatology and Venereology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China.", "Xinjiang Clinical Medical Research Center for Dermatology and Venereology, Urumqi, China.", "Xinjiang Key Laboratory of Dermatology Research, Urumqi, China." ], "article_type": "Research Article", "arxiv": null, "author_total": 7, "authors": [ { "affs": [ 0, 1, 2 ], "name": "Yu Zhang", "orcid": "0009-0005-2420-9604" }, { "affs": [ 0, 1, 2 ], "name": "Peng Wang" }, { "affs": [ 0, 1, 2 ], "name": "Jingzhan Zhang" }, { "affs": [ 0, 1, 2 ], "name": "Yunying Wang" }, { "affs": [ 0, 1, 2 ], "name": "Tingting Li" }, { "affs": [ 0, 1, 2 ], "name": "Yuan Ding" }, { "affs": [ 0, 1, 2 ], "name": "Xiaojing Kang", "orcid": "0000-0002-3081-406X" } ], "bibtex": "https://research.draconitic.com/paper/42rs072ng4dvy.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014615", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014615", "id": "42rs072ng4dvy", "issns": [ "1553-7374", "1553-7366" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014615", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2730|Viral-associated cancers and disorders" ], [ "plos", "/Biology and life sciences/Biogeography/Phylogeography" ], [ "plos", "/Biology and life sciences/Evolutionary biology/Population genetics/Phylogeography" ], [ "plos", "/Biology and life sciences/Genetics/Population genetics/Phylogeography" ], [ "plos", "/Biology and life sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Herpesviruses/Kaposi's sarcoma-associated herpesvirus" ], [ "plos", "/Biology and life sciences/Molecular biology/Molecular biology techniques/Genotyping" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/DNA viruses/Herpesviruses/Kaposi's sarcoma-associated herpesvirus" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Herpesviruses/Kaposi's sarcoma-associated herpesvirus" ], [ "plos", "/Biology and life sciences/Population biology/Population genetics/Phylogeography" ], [ "plos", "/Earth sciences/Geography/Biogeography/Phylogeography" ], [ "plos", "/Ecology and environmental sciences/Biogeography/Phylogeography" ], [ "plos", "/Medicine and health sciences/Clinical medicine/Signs and symptoms/Edema" ], [ "plos", "/Medicine and health sciences/Clinical medicine/Signs and symptoms/Inflammation" ], [ "plos", "/Medicine and health sciences/Epidemiology/Medical risk factors/Cancer risk factors" ], [ "plos", "/Medicine and health sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Medicine and health sciences/Oncology/Cancer risk factors" ], [ "plos", "/Medicine and health sciences/Oncology/Cancers and neoplasms" ], [ "plos", "/Medicine and health sciences/Oncology/Cancers and neoplasms/Sarcoma/Kaposi sarcoma" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Herpesviruses/Kaposi's sarcoma-associated herpesvirus" ], [ "plos", "/Research and analysis methods/Molecular biology techniques/Genotyping" ] ], "openalex": "W7220839769", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014615&type=printable", "pmcid": "PMC13660985", "pmid": "42842712", "published": "2026-10-07", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/42rs072ng4dvy.ris", "sources": [ { "first_seen": "2026-10-30T12:17:30Z", "native_id": "10.1371/journal.ppat.1014615", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014615" }, { "first_seen": "2026-10-30T12:18:02Z", "native_id": "MED:42842712", "source": "europepmc", "url": "https://europepmc.org/article/MED/42842712" } ], "subjects": [ { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "medicine", "origin": "plos:oncology", "subfield": "oncology" } ], "title": "KSHV K15 genetic heterogeneity is associated with Kaposi sarcoma aggressiveness through modulation of the host inflammatory microenvironment", "title_text": "KSHV K15 genetic heterogeneity is associated with Kaposi sarcoma aggressiveness through modulation of the host inflammatory microenvironment", "type": "peer-reviewed", "updated_at": "2026-10-30T12:18:02Z", "url": "https://research.draconitic.com/paper/42rs072ng4dvy", "venue": "PLOS Pathogens", "versions": [] }