{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:46:19Z","timestamp":1791917179400,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014615","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000}}],"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016079","name":"Xinjiang Uygur Autonomous Region","doi-asserted-by":"publisher","award":["2024B03039\u20431"],"award-info":[{"award-number":["2024B03039\u20431"]}],"id":[{"id":"10.13039\/100016079","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Xinjiang Uygur Autonomous Region","award":["2024B03039\u20432"],"award-info":[{"award-number":["2024B03039\u20432"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    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\u2019s sarcoma-associated herpesvirus (KSHV)\n                    <jats:italic>K15<\/jats:italic>\n                    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\u2014categorized as localized or disseminated\u2014by integrating anatomical criteria from the ACTG and Krigel classifications. Using causal mediation analysis to quantify the \u201cGenotype\u2013Inflammation\u2013Edema\u201d association, we identified the\n                    <jats:italic>K15<\/jats:italic>\n                    M-genotype (72.8%) was independently associated with a hyper-inflammatory phenotype. This revealed a Viral\u2013Clinical Paradox: despite significantly lower HIV coinfection rates compared to P-carriers (10.3% vs. 27.5%;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.009), M-carriers exhibited an elevated Systemic Immune-Inflammation Index (SII) and severe clinical edema. Mediation analysis confirmed that the SII significantly mediated 29.0% (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.009) 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;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.003). 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;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.0001). Our results suggest that the\n                    <jats:italic>K15<\/jats:italic>\n                    M-genotype is associated with increased KS severity\n                    <jats:italic>via<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014615","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:53:28Z","timestamp":1791395608000},"page":"e1014615","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["KSHV K15 genetic heterogeneity is associated with Kaposi sarcoma aggressiveness through modulation of the host inflammatory microenvironment"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2420-9604","authenticated-orcid":true,"given":"Yu","family":"Zhang","sequence":"first","affiliation":[{"name":"People\u2019s Hospital of Xinjiang Uygur Autonomous Region","place":["Urumqi, China"],"department":["Department of Dermatology and Venereology"]},{"name":"Xinjiang Clinical Medical Research Center for Dermatology and Venereology","place":["Urumqi, China"]},{"name":"Xinjiang Key Laboratory of Dermatology Research","place":["Urumqi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[{"name":"People\u2019s Hospital of Xinjiang Uygur Autonomous Region","place":["Urumqi, China"],"department":["Department of Dermatology and Venereology"]},{"name":"Xinjiang Clinical Medical Research Center for Dermatology and Venereology","place":["Urumqi, China"]},{"name":"Xinjiang Key Laboratory of Dermatology Research","place":["Urumqi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingzhan","family":"Zhang","sequence":"additional","affiliation":[{"name":"People\u2019s Hospital of Xinjiang Uygur Autonomous Region","place":["Urumqi, China"],"department":["Department of Dermatology and Venereology"]},{"name":"Xinjiang Clinical Medical Research Center for Dermatology and Venereology","place":["Urumqi, China"]},{"name":"Xinjiang Key Laboratory of Dermatology Research","place":["Urumqi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunying","family":"Wang","sequence":"additional","affiliation":[{"name":"People\u2019s Hospital of Xinjiang Uygur Autonomous Region","place":["Urumqi, China"],"department":["Department of Dermatology and Venereology"]},{"name":"Xinjiang Clinical Medical Research Center for Dermatology and Venereology","place":["Urumqi, China"]},{"name":"Xinjiang Key Laboratory of Dermatology Research","place":["Urumqi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Li","sequence":"additional","affiliation":[{"name":"People\u2019s Hospital of Xinjiang Uygur Autonomous Region","place":["Urumqi, China"],"department":["Department of Dermatology and Venereology"]},{"name":"Xinjiang Clinical Medical Research Center for Dermatology and Venereology","place":["Urumqi, China"]},{"name":"Xinjiang Key Laboratory of Dermatology Research","place":["Urumqi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Ding","sequence":"additional","affiliation":[{"name":"People\u2019s Hospital of Xinjiang Uygur Autonomous Region","place":["Urumqi, China"],"department":["Department of Dermatology and Venereology"]},{"name":"Xinjiang Clinical Medical Research Center for Dermatology and Venereology","place":["Urumqi, China"]},{"name":"Xinjiang Key Laboratory of Dermatology Research","place":["Urumqi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3081-406X","authenticated-orcid":true,"given":"Xiaojing","family":"Kang","sequence":"additional","affiliation":[{"name":"People\u2019s Hospital of Xinjiang Uygur Autonomous Region","place":["Urumqi, China"],"department":["Department of Dermatology and Venereology"]},{"name":"Xinjiang Clinical Medical Research Center for Dermatology and Venereology","place":["Urumqi, China"]},{"name":"Xinjiang Key Laboratory of Dermatology Research","place":["Urumqi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"issue":"1","key":"ppat.1014615.ref001","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1186\/s13256-022-03637-8","article-title":"Iatrogenic Kaposi sarcoma of the small bowel in Crohn\u2019s disease following short-term use of immunomodulators: a case report and review of the literature","volume":"16","author":"PJ Wu","year":"2022","journal-title":"J Med Case Rep"},{"issue":"1","key":"ppat.1014615.ref002","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.clindermatol.2025.09.013","article-title":"Updates on Kaposi sarcoma","volume":"44","author":"KZ Htet","year":"2026","journal-title":"Clin Dermatol"},{"issue":"1","key":"ppat.1014615.ref003","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12981-017-0156-9","article-title":"Clinical characteristics, predictors of immune reconstitution inflammatory syndrome and long-term prognosis in patients with Kaposi sarcoma","volume":"14","author":"P Volkow","year":"2017","journal-title":"AIDS Res Ther"},{"issue":"1","key":"ppat.1014615.ref004","doi-asserted-by":"crossref","first-page":"19738","DOI":"10.1038\/s41598-025-04695-w","article-title":"Correlation between ADGRV1 expression and clinical pathological and prognostic features in breast cancer","volume":"15","author":"L Wang","year":"2025","journal-title":"Sci Rep"},{"issue":"11","key":"ppat.1014615.ref005","doi-asserted-by":"crossref","first-page":"3609","DOI":"10.1038\/s41591-025-03711-w","article-title":"Cancer treatment paradigms in the precision medicine era","volume":"31","author":"V Subbiah","year":"2025","journal-title":"Nat Med"},{"issue":"12","key":"ppat.1014615.ref006","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.3390\/cells13121023","article-title":"Recent advances in molecular and genetic research on uveal melanoma","volume":"13","author":"A Fuentes-Rodriguez","year":"2024","journal-title":"Cells"},{"issue":"15","key":"ppat.1014615.ref007","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.1200\/JCO.2003.10.162","article-title":"AIDS-related Kaposi\u2019s sarcoma: evaluation of potential new prognostic factors and assessment of the AIDS Clinical Trial Group Staging System in the Haart era--the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Patients Naive from Antiretrovirals","volume":"21","author":"G Nasti","year":"2003","journal-title":"J Clin Oncol"},{"issue":"6","key":"ppat.1014615.ref008","first-page":"531","article-title":"Kaposi\u2019s sarcoma: a new staging classification","volume":"67","author":"RL 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guidelines: the example of TRIPOD for assessing completeness of reporting of prediction model studies","volume":"9","author":"P Heus","year":"2019","journal-title":"BMJ Open"},{"issue":"7","key":"ppat.1014615.ref030","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1012338","article-title":"Sequencing of Kaposi\u2019s Sarcoma Herpesvirus (KSHV) genomes from persons of diverse ethnicities and provenances with KSHV-associated diseases demonstrate multiple infections, novel polymorphisms, and low intra-host variance","volume":"20","author":"VA Marshall","year":"2024","journal-title":"PLoS Pathog"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1014615","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000}}],"container-title":["PLOS 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