KSHV K15 genetic heterogeneity is associated with Kaposi sarcoma aggressiveness through modulation of the host inflammatory microenvironment.

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.