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Abstract：
In this study, we investigated the effects of human type I consensus interferon (IFN-con1) (Amgen) gene transfer into body cavity-based lymphomas (BCBL)-1 cells, which are latently infected with Kaposi\'s sarcoma-associated herpesvirus (KSHV) human herpesvirus-8 (HHV-8). Both the basal and 12-O-tetradecanoyl phorbol-13-acetate (TPA)-stimulated production of KSHV/HHV-8 mature virions was strongly inhibited in genetically modified IFN-producing BCBL-1 cells as compared with parental or control transduced counterparts. A similar inhibition was obtained on treatment of parental BCBL-1 cells with exogenous IFN-con1. The reduction in KSHV/HHV-8 production was associated with a decrease in the basal and TPA-stimulated intracellular amount of the linear form of the viral genome. Interestingly, 25%40% of the IFN-producing BCBL-1 cell population underwent spontaneous apoptosis in vitro. TPA treatment, which did not significantly affect the viability of the parental and control BCBL-1 cells, resulted in the apoptotic death of up to 70% of the IFN-producing cell population. Addition of exogenous IFN-con1 to parental BCBL-1 cells produced similar effects, although less intense. Injection of either parental or control-transduced BCBL-1 cells into SCID mice resulted in progressively growing tumors characterized by an unusually high level of tumor angiogenesis. In contrast, complete tumor regression was observed in all the mice injected either subcutaneously (s.c.) or intraperitoneally (i.p.) with the IFN-producing BCBL-1 cells. These results represent the first evidence that type I IFN can counteract the activation of a productive herpesvirus infection in latently infected tumor cells by the induction of apoptosis, providing an interesting link between the antiviral and antitumor activities of this cytokine. These data suggest the possible advantages of strategies of type I IFN gene transfer (with respect to the use of the exogenous cytokine) for the treatment of patients with some HHV-8-induced malignancies.
摘要：
在这项研究中,我们研究了人类I型共有干扰素（IFN-con1）（Amgen）基因转移到体腔基淋巴瘤（BCBL）-1细胞的影响，潜伏感染卡波西肉瘤相关疱疹病毒（KSHV）人疱疹病毒8（HHV-8）。与亲本或对照转导的对应物相比，在遗传修饰的产生IFN的BCBL-1细胞中，KSHV/HHV-8成熟病毒体的基础和12-O-十四酰基佛波醇-13-乙酸酯（TPA）刺激的产生均受到强烈抑制。用外源IFN-con1处理亲本BCBL-1细胞获得了类似的抑制。KSHV/HHV-8产生的减少与病毒基因组线性形式的基础和TPA刺激的细胞内量的减少有关。有趣的是,25%40%的产生IFN的BCBL-1细胞群在体外经历自发凋亡。TPA治疗,没有显著影响亲本和对照BCBL-1细胞的活力，导致高达70％的IFN产生细胞群的凋亡死亡。外源IFN-con1添加到亲本BCBL-1细胞产生类似的效果，虽然不那么激烈。将亲本或对照转导的BCBL-1细胞注射到SCID小鼠中导致逐渐生长的肿瘤,其特征在于异常高水平的肿瘤血管生成。相比之下,在皮下(s.c.)或腹膜内(i.p.)注射产生IFN的BCBL-1细胞的所有小鼠中观察到完全的肿瘤消退。这些结果代表了第一个证据，即I型IFN可以通过诱导细胞凋亡来抵消潜伏感染肿瘤细胞中生产性疱疹病毒感染的激活。在这种细胞因子的抗病毒和抗肿瘤活性之间提供了有趣的联系。这些数据表明，I型IFN基因转移策略（相对于使用外源性细胞因子）治疗某些HHV-8诱导的恶性肿瘤的患者可能具有优势。
