Live KSHV virus induces a dose-dependent increase in β-hexosaminidase release from LAD2 (A) and LUVA (B) cells within 1 hr (n=3, mean ±SEM). Difference in percent β-hexosaminidase release was analyzed by using 1-way ANOVA, followed by Bonnferroni multiple comparison test. **p<0.01, ***p<0.001. (C-H) Activated, degranulating and degranulated MCs are associated with KSHV LANA+ KS cell nuclei and EC nuclei in vivo; HIV+ KSHV LANA+ KS tissues double stained for MC-specific tryptase (cytoplasm-red) and KSHV LANA (nucleus-brown) demonstrate: (C) A resting MC from HIV+ control tissue is shown for size comparison; (D) HIV+ early KS skin patch lesion demonstrates an enlarged, activated MC showing abundant tryptase filled cytoplasm and enlarged nucleus compared to (C); (E) MC directional tryptase degranulation. An activated, elongated and vacuolated MC produces a narrow stream of discrete tryptase+ granules (red) from the MC tip directed toward the enlarged intravascular KSHV LANA infected EC nuclei (brown); (F) MC mass tryptase granule degranulation (box) within a tissue bundle of proliferating KSHV infected spindle cells. Discrete tryptase+ granules flood the infected spindle cell bundle. (G) Partial and complete MC degranulation between compact KS spindle cells in developing KS nodular lesion. Note the MC ‘ghost’ lobulated LANA+ nucleus and foamy cytoplasm (upper box) and a partially degranulated MC (lower box); (H) Prussian blue hemosiderin granules are a persistent feature of MC degranulation in KS lesions. Scale bar 50 μm.