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

KSHV（卡波西肉瘤相关疱疹病毒）的作用

• 批准号: 7070796
• 负责人: Giovanna Tosato
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7070796
• 关键词: Kaposi' s sarcoma; apoptosis; cytokine receptors; enzyme linked immunosorbent assay; hematopoiesis; human herpesvirus 8; interleukin 6; laboratory mouse; lymphoma; neutralizing antibody; phosphorylation; survivin; tissue /cell culture; transfection; vascular endothelial growth factors; viral carcinogenesis

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.

Kaposi的肉瘤相关疱疹病毒（KSHV）与Kaposi的肉瘤（KS），一级积液淋巴瘤（PEL）和Castelman病的一部分有关。我们一直有兴趣阐明KSHV相关疾病和探索治疗阶层的致病机制。 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，并对人和小鼠IL-6表现出约25％的氨基酸身份，这表明这可能是有用细胞基因的病毒盗版的结果。通过体外和体内实验，我们表征了VIL-6受体，并描述了VIL-6的生物学活性。特别是，接种VIL-6显示的小鼠在髓样，红细胞和杂志核细胞谱系中显示出增加的造血。脾脏和淋巴结中的浆细胞增多；肝肾上腺肿和多克隆高γ-球蛋白血症。小鼠中VIL-6的过表达是肿瘤的，部分是由于VIL-6诱导血管内皮生长因子（VEGF）。针对VEGF的中和抗体可阻止感染KSHV并产生VIL-6的PEL的发展。使用针对VIL-6的新产生的单克隆抗体以及使用这些抗体开发的灵敏的VIL-6 ELISA，我们测量了KSHV相关疾病中的血清VIL-6水平，以及与疾病进展和对治疗反应相关的循环VIL-6水平。 GP130用作VIL-6受体。通过GP130信号传导促进STAT3磷酸化。 PEL细胞表达组成性活性STAT3。用STAT3的主要负面形式转染的PEL细胞或用STAT3抑制剂AG490治疗的PEL细胞因与抗凋亡蛋白Survivin的表达降低相关的细胞凋亡而迅速死亡。 pel细胞中源性的过表达使它们对STAT3抑制引起的凋亡具有抵抗力。因此，通过细胞因子的表达，KSHV可以促进STAT3磷酸化和抗凋亡蛋白存活的表达，从而确保病毒感染细胞的生存扩展。 STAT3激活与Survivin表达之间的联系可能在设计新的治疗方法的设计中有用，以治疗KSHV相关和其他恶性肿瘤。在相关研究中，我们研究了与具有其他形式的T细胞免疫缺陷患者相反的艾滋病患者Kaposi肉瘤频率增加的潜在原因。我们已经发现，HIV-1 TAT蛋白和TAT的片段，其中包括12种碱性肽，可以用KSHV促进内皮细胞感染，KSHV是Kaposi的肉瘤的病因学剂。因此，HIV-1似乎通过促进KSHV靶细胞感染而直接有助于Kaposi肉瘤的发病机理。