The Lymphatic Cell Environment Promotes Kaposi Sarcoma Development by Prox1-Enhanced Productive Lytic Replication of Kaposi Sarcoma Herpes Virus.
The Lymphatic Cell Environment Promotes Kaposi Sarcoma Development by Prox1-Enhanced Productive Lytic Replication of Kaposi Sarcoma Herpes Virus.
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DOI：
10.1158/0008-5472.can-19-3105
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发表时间：
2020-08-01
期刊：
影响因子：
11.2
通讯作者：
Hong YK
中科院分区：
文献类型：
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作者：
Choi D;Park E;Kim KE;Jung E;Seong YJ;Zhao L;Madhavan S;Daghlian G;Lee HH;Daghlian PT;Daghlian S;Bui K;Koh CJ;Wong AK;Cho IT;Hong YK
卡波西肉瘤（KS）是hiv阳性个体中最常见的癌症，由KS相关疱疹病毒（KSHV）引起。据信，少量潜伏感染的KS肿瘤细胞会自发裂解再激活，产生病毒后代以感染新细胞。在这里，我们使用匹配的供体来源的人真皮血液和淋巴内皮细胞（分别为BEC和LEC）来显示kshv感染的BEC随着它们的增殖而逐渐失去病毒基因组。与此形成鲜明对比的是，kshv感染的LEC主要进入裂解复制，进行细胞裂解并释放新病毒。持续的细胞裂解和重新感染使LEC培养物在较长时间内保持感染。由于LEC对裂解复制的强烈倾向，尽管单个宿主细胞因裂解而死亡，但LEC仍能维持病毒作为一个群体。淋巴发育的主调控因子Prox1结合RTA基因的启动子上调其表达，并与RTA蛋白物理相互作用共调控裂解基因。因此，LEC可能作为一个熟练的病毒库，为肿瘤起源细胞，以及可能导致KS肿瘤的BEC和间充质干细胞的持续从头感染提供病毒后代。我们的研究揭示了BEC和LEC之间宿主细胞行为的巨大差异，并定义了淋巴细胞环境支持KS肿瘤持续感染的潜在机制。
Kaposi’s sarcoma (KS) is the most common cancer in HIV-positive individuals and is caused by KS-associated herpesvirus (KSHV). It is believed that a small number of latently infected KS tumor cells undergo spontaneous lytic reactivation to produce viral progeny for infection of new cells. Here we use matched donor-derived human dermal blood and lymphatic endothelial cells (BEC and LEC, respectively) to show that KSHV-infected BEC progressively lose viral genome as they proliferate. In sharp contrast, KSHV-infected LEC predominantly entered lytic replication, underwent cell lysis, and released new virus. Continuous lytic cell lysis and de novo infection allowed LEC culture to remain infected for a prolonged time. Due to the strong propensity of LEC toward lytic replication, LEC maintained virus as a population, despite the death of individual host cells from lytic lysis. The master regulator of lymphatic development Prox1 bound the promoter of the RTA gene to upregulate its expression and physically interacted with RTA protein to coregulate lytic genes. Thus, LEC may serve as a proficient viral reservoir that provides viral progeny for continuous de novo infection of tumor origin cells, and potentially BEC and mesenchymal stem cells, which give rise to KS tumors. Our study reveals drastically different host cell behaviors between BEC and LEC and defines the underlying mechanisms of the lymphatic cell environment supporting persistent infection in KS tumors.