A Role for KSHV (Kaposi's Sarcoma-associated Herpesvirus

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。我们一直有兴趣阐明KSHV相关疾病的发病机制和探索治疗策略。KSHV编码的细胞因子vIL-6一直是我们研究的重点。它主要在病毒复制过程中产生，与人和小鼠IL-6具有约25%的氨基酸同一性，表明它可能是有用细胞基因的病毒盗版的结果。通过体内外实验，我们对vIL-6受体进行了表征，并描述了vIL-6的生物学活性。特别是，接种vIL-6的小鼠在髓系、红系和巨核细胞谱系中表现出造血增加;脾和淋巴结中的浆细胞增多;肝脾肿大和多克隆高丙种球蛋白血症。vIL-6在小鼠中的过表达是致瘤的，部分是由于vIL-6诱导血管内皮生长因子（VEGF）。针对VEGF的中和抗体可预防KSHV感染的PEL的发展并产生vIL-6。使用新产生的抗vIL-6的单克隆抗体和用这些抗体开发的敏感的vIL-6 ELISA，我们测量了KSHV相关疾病的血清vIL-6水平，并将循环vIL-6水平与疾病进展和对治疗的反应相关联。gp 130作为vIL-6受体。通过gp 130的信号传导促进STAT 3磷酸化。PEL细胞表达组成型活性STAT 3。用显性负性形式的STAT 3转染或用STAT 3抑制剂AG 490处理的PEL细胞由于与抗凋亡蛋白Survivin表达减少相关的凋亡而迅速死亡。Survivin在PEL细胞中的过表达使其对STAT 3抑制诱导的凋亡具有抗性。因此，通过细胞因子的表达，KSHV可以促进STAT 3磷酸化和抗凋亡蛋白Survivin的表达，确保病毒感染细胞的延长存活。STAT 3激活和Survivin表达之间的联系可能有助于设计治疗KSHV相关和其他恶性肿瘤的新治疗方法。在相关研究中，我们调查了艾滋病患者卡波西肉瘤发生率高于其他形式T细胞免疫缺陷患者的潜在原因。我们已经发现HIV-1达特蛋白和达特的一个片段，其中包括一段12个碱性肽，可以促进内皮细胞感染KSHV，卡波西肉瘤的病原体。因此，HIV-1似乎通过促进靶细胞感染KSHV直接导致卡波西肉瘤的发病机制。

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. We have been interested in elucidating the pathogenetic mechanisms underlying KSHV-associated diseases and exploring stratetegies for treatment. The KSHV encoded cytokine vIL-6 has been a focus of our studies. It is produced predominantly during viral replication and exhibits approximately 25% amino acids identity to human and mouse 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 vIL-6 receptor and described the biological activities of vIL-6. In particular, mice inoculated with vIL-6 display increased hematopoiesis in the myeloid, erythroid, and magakaryocytic lineages; plasmacytosis in the spleen and lymph nodes; hepatosplenomegaly, and polyclonal hypergammaglobulinemia. Over-expression of vIL-6 in mice is tumorigenic, in part due to vIL-6 induction of vascular endothelial growth factor (VEGF). Neutralizing antibodies directed at VEGF prevent the development of PEL that is KSHV infected and produces vIL-6. Using newly generated monoclonal antibodies against vIL-6 and a sensitive vIL-6 ELISA developed with these antibodies, we have measured serum vIL-6 levels in KSHV-associated diseases, and correlated circulating vIL-6 levels with disease progression and response to therapy. gp130 serves as the vIL-6 receptor. Signaling through gp130 promotes STAT3 phosphorylation. PEL cells express a constitutively active STAT3. PEL cells transfected with a dominant negative form of STAT3 or treated with the STAT3 inhibitor AG490 rapidly die by apoptosis associated with diminished expression of the anti-apoptotic protein Survivin. Over-expression of Survivin in PEL cells renders them resistant to apoptosis induced by STAT3 inhibition. Thus, through the expression of cytokines, KSHV can promote STAT3 phosphorylation and expression of the anti-apoptotic protein Survivin ensuring extended survival of the virally infected cells. The linkage between STAT3 activation and Survivin expression may be useful in the design of new therapeutic approaches for the treatment of KSHV-associated and other malignancies. In related studies, we have investigated the potential reasons undelying the increased frequency of Kaposi's sarcoma in patients with AIDS as opposed to patients with other forms of T-cell immunodeficiency. We have discovered that HIV-1 Tat protein and a fragment of Tat, which includes a stretch of 12 basic peptides, can promote endothelial cell infection with KSHV, the etiologic agent of Kaposi's sarcoma. Thus, HIV-1 appears to directly contribute to the pathogenesis of Kaposi's sarcoma by promoting target cell infection with KSHV.