KSHV in Pathogenesis of Maligancies

卡波西肉瘤相关疱疹病毒(KSHV)与卡波西肉瘤(KS)、原发性渗出性淋巴瘤(PEL)和部分Castelman病的发生有关。KSHV编码几种细胞因子和趋化素样蛋白，包括白介素6(IL-6)的同源物。病毒(V)IL-6主要在病毒复制过程中产生，与人和小鼠IL-6的氨基酸同源性约为25%，这表明它可能是病毒盗用有用的细胞基因的结果。通过体内外实验，我们对VIL-6的生物学活性进行了表征。接种VIL-6的小鼠表现出髓系、红系和巨核系的造血量增加，脾和淋巴结的浆细胞增多，肝脾肿大和多克隆性高丙种球蛋白血症。我们发现，表达VIL-6的成纤维细胞比对照细胞更快地产生肿瘤，并将肿瘤生长的增加与VIL-6诱导血管内皮生长因子(VEGF)联系起来。此外，使用针对血管内皮生长因子的中和抗体，我们证实了血管内皮生长因子是小鼠实验性PEL发育所必需的。利用新制备的抗VIL-6的单抗，建立了敏感的VIL-6酶联免疫吸附试验。这种方法可以评估KSHV相关疾病的血清VIL-6水平，并将循环VIL-6水平与疾病进展和治疗反应相关联。体外实验用于研究VIL-6受体的利用。与细胞IL-6不同，VIL-6被发现直接与gp130结合。一组VIL-6特异性中和抗体被用作分析VIL-6结构/功能关系的工具。因此，VIL-6是一种多功能的病毒细胞因子，通过共同的gp130受体链发挥作用，在某些KSHV相关疾病的发病机制中起关键作用。

Kaposi's sarcoma associated herpesvirus (KSHV) has been linked to the development of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and a proportion of Castelman's disease. KSHV encodes several cytokine-and chemokine-like proteins, including a homologue of interleukin-6 (IL-6). Viral (v) IL-6, produce predominantly during viral replication, exhibits approximately 25% amino acids identity to human and murine IL-6, suggesting that it may be the result of viral piracy of a useful cellular gene. Through experiments in vitro and in vivo, we have characterized the biological activities of vIL-6. Mice inoculated with vIL-6 displayed increased hematopoiesis in the myeloid, erythroid, and magakaryocytic lineages; plasmacytosis in the spleen and lymph nodes; hepatosplenomegaly, and polyclonal hypergammaglobulinemia. We determined that vIL-6 expressing fibroblasts give rise to tumors more rapidly than control cells, and linked increased tumor growth to vIL-6 induction of vascular endothelial growth factor (VEGF). In addition, using neutralizing antibodies directed at VEGF, we established that VEGF is required for experimental PEL development in mice. Using newly generated monoclonal antibodies against vIL-6, a sensitive vIL-6 ELISA was established. This assay permitted to evaluate serum vIL-6 levels in KSHV-associated diseases, and correlate circulating vIL-6 levels with disease progression and response to therapy. In vitro experiments were used to study vIL-6 receptor utilization. Unlike cellular IL-6, vIL-6 directly was found to bind to gp130. A panel of vIL-6-specific neutralizing antibodies were used as tools to dissect vIL-6 structure/function relationships. Thus, vIL-6, a multifunctional viral cytokine acting through the common gp130 receptor chain, is critically involved in the pathogenesis of certain KSHV associated diseases.