Long-term infection and transformation of dermal microvascular endothelial cells by human herpesvirus 8
Long-term infection and transformation of dermal microvascular endothelial cells by human herpesvirus 8
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DOI：
10.1128/jvi.73.8.6892-6902.1999
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发表时间：
1999-08-01
影响因子：
5.4
通讯作者：
Nelson, JA
中科院分区：
文献类型：
--
作者：
Moses, AV;Fish, KN;Nelson, JA
人类疱疹病毒8型(HHV8)原位感染卡波西肉瘤(KS)梭形细胞，以及被认为是梭形细胞前体的皮损内皮细胞。HHV8基因组中含有多个癌基因，提示内皮细胞和梭形细胞感染可诱导细胞转化和肿瘤发生，促进RS病变的形成。为了探讨HHV8感染内皮细胞在KS发病中的作用，我们利用真皮微血管内皮细胞建立了一种体外模型，该模型利用真皮微血管内皮细胞支持显著的HHV8感染。与现有的用于研究HHV8致病机制的体外系统相比，大多数真皮内皮细胞都感染了HHV8，并且病毒基因组被无限期地保持。感染主要是潜伏的，有一小部分细胞支持裂解复制，潜伏期对裂解诱导刺激有反应，感染的内皮细胞发展成类似于KS病变细胞的纺锤形，并表现出转化表型的特征，包括失去接触抑制和获得锚定无关的生长。这些结果描述了一个相关的模型系统，用于在体外研究病毒与宿主的相互作用，并证明HHV8能够诱导感染的内皮细胞发生类似于体内KS梭形细胞特征的表型变化。因此，我们的结果与HHV8在KS发病机制中的直接作用是一致的。
Human herpesvirus 8 (HHV8) infects Kaposi's sarcoma (KS) spindle cells in situ, as well as the lesional endothelial cells considered to be spindle cell precursors. The HHV8 genome contains several oncogenes, suggesting that infection of endothelial and spindle cells could induce cellular transformation and tumorigenesis and promote the formation of RS lesions. To investigate the potential of HHV8 infection of endothelial cells to contribute to the development of KS, we have developed an in vitro model utilizing dermal microvascular endothelial cells that support significant HHV8 infection. In contrast to existing in vitro systems used to study HHV8 pathogenesis, the majority of dermal endothelial cells are infected with HHV8 and the viral genome is maintained indefinitely. Infection is predominantly latent, with a small percentage of cells supporting lytic replication, and latency is responsive to lytic induction stimuli, Infected endothelial cells develop a spindle shape resembling that of KS lesional cells and show characteristics of a transformed phenotype, including loss of contact inhibition and acquisition of anchorage-independent growth. These results describe a relevant model system in which to study virus-host interactions in vitro and demonstrate the ability of HHV8 to induce phenotypic changes in infected endothelial cells that resemble characteristics of KS spindle cells in vivo. Thus, our results are consistent with a direct role for HHV8 in the pathogenesis of KS.