NF-κB inhibits gammaherpesvirus lytic replication
NF-κB inhibits gammaherpesvirus lytic replication
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DOI：
10.1128/jvi.77.15.8532-8540.2003
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发表时间：
2003-08-01
影响因子：
5.4
通讯作者：
Sun, R
中科院分区：
文献类型：
--
作者：
Brown, HJ;Song, MJ;Sun, R
鼻咽癌、卡波西肉瘤和B细胞淋巴瘤是与γ疱疹病毒感染相关的人类恶性肿瘤。该病毒家族的成员的特征在于它们在淋巴细胞中建立潜伏感染的能力。潜伏病毒基因组表达很少的基因产物。因此，受感染的细胞很难被宿主免疫系统识别，从而使病毒能够长时间持续存在。我们试图确定细胞特异性因子，使这些病毒将其生命周期从生产性复制重定向到潜伏期。我们发现，细胞转录因子NF-κ B可以调节这一过程。上皮细胞和成纤维细胞支持活性（裂解性）γ疱疹病毒复制，并具有低NF-κ B活性。然而，在这些细胞中NF-κ B的过表达抑制γ疱疹病毒鼠疱疹病毒68（MRV 68）的复制。此外，NF-κ B的过表达抑制来自MHV 68和人γ疱疹病毒卡波西肉瘤相关疱疹病毒（KSHV）和EB病毒（EBV）的裂解启动子的活化。在KSHV或EBV潜伏感染的淋巴细胞中，NF-κ B活性水平很高，用抗病毒药物治疗这些细胞可以提高NF-κ B活性。NF-κ B抑制剂导致与病毒再活化一致的裂解蛋白合成。这些结果表明，高水平的NF-κ B可以抑制γ疱疹病毒裂解复制，因此可能有助于淋巴细胞中病毒潜伏期的建立和维持。他们还表明，NF-κ B可能是破坏病毒潜伏期的新靶点，因此可以治疗γ疱疹病毒相关的恶性肿瘤。
Nasopharyngeal carcinoma, Kaposi's sarcoma, and B-cell lymphomas are human malignancies associated with gammaherpesvirus infections. Members of this virus family are characterized by their ability to establish latent infections in lymphocytes.. The latent viral genome expresses very few gene products. The infected cells are therefore poorly recognized by the host immune system, allowing the virus to persist for long periods of time. We sought to identify the cell-specific factors that allow these viruses to redirect their life cycle from productive replication to latency. We find that the cellular transcription factor NF-kappaB can regulate this process. Epithelial cells and fibroblasts support active (lytic) gammaherpesvirus replication and have low NF-kappaB activity. However, overexpression of NF-kappaB in these cells inhibits the replication of the gammaherpesvirus murine herpesvirus 68 (MRV68). In addition, overexpression of NF-kappaB inhibits the activation of lytic promoters from MHV68 and human gammaherpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). In lymphocytes latently infected with KSHV or EBV, the level of NF-kappaB activity is high, and treatment of these cells with an. NF-kappaB inhibitor leads to lytic protein synthesis consistent with virus reactivation. These results suggest that high levels of NF-kappaB can inhibit gammaherpesvirus lytic replication and may therefore contribute to the establishment and maintenance of viral latency in lymphocytes. They also suggest that NF-kappaB may be a novel target for the disruption of virus latency and therefore the treatment of gammaherpesvirus-related malignancies.