The human tumor viruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) establish persistent infections in B cells. KSHV is linked to primary effusion lymphoma (PEL), and 90% of PELs also contain EBV. Studies on persistent KSHV infection in vivo and the role of EBV co-infection in PEL development have been hampered by the absence of small animal models. We developed mice reconstituted with human immune system components as a model for KSHV infection and find that EBV/KSHV dual infection enhanced KSHV persistence and tumorigenesis. Dual-infected cells displayed a plasma cell-like gene expression pattern similar to PELs. KSHV persisted in EBV-transformed B cells and was associated with lytic EBV gene expression, resulting in increased tumor formation. Evidence of elevated lytic EBV replication was also found in EBV/KSHV dually infected lymphoproliferative disorders in humans. Our data suggest that KSHV augments EBV-associated tumorigenesis via stimulation of lytic EBV replication.

人类肿瘤病毒 Epstein-Barr 病毒 (EBV) 和卡波西肉瘤相关疱疹病毒 (KSHV) 在 B 细胞中建立持续感染。KSHV 与原发性渗出性淋巴瘤 (PEL) 相关，90% 的 PEL 也含有 EBV。体内持续性KSHV感染的研究由于缺乏小动物模型，EBV 共感染在 PEL 发展中的作用受到阻碍。我们开发了用人类免疫系统成分重组的小鼠作为 KSHV 感染的模型，发现 EBV/KSHV 双重感染增强了 KSHV 的持久性和肿瘤发生。双重感染的细胞显示出类似于 PEL 的浆细胞样基因表达模式。KSHV 持续存在于 EBV 转化的 B 细胞中，并与裂解 EBV 基因表达相关，导致肿瘤形成增加。在人类 EBV/KSHV 双重感染的淋巴组织增生性疾病中也发现了裂解性 EBV 复制升高的证据。我们的数据表明，KSHV 通过刺激裂解性 EBV 复制来增强 EBV 相关的肿瘤发生。