Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi’s sarcoma and hyperinflammatory lymphoproliferative disorders. Understanding the mechanism by which KSHV increases the infected cell population is crucial for curing KSHV-associated diseases. Using scRNA-seq, we demonstrate that KSHV preferentially infects CD14+ monocytes, sustains viral lytic replication through the viral interleukin-6 (vIL-6), which activates STAT1 and 3, and induces an inflammatory gene expression program. To study the role of vIL-6 in monocytes upon KSHV infection, we generated recombinant KSHV with premature stop codon (vIL-6(-)) and its revertant viruses (vIL-6(+)). Infection of the recombinant viruses shows that both vIL-6(+) and vIL-6(-) KSHV infection induced indistinguishable host anti-viral response with STAT1 and 3 activations in monocytes; however, vIL-6(+), but not vIL-6(-), KSHV infection promoted the proliferation and differentiation of KSHV-infected monocytes into macrophages. The macrophages derived from vIL-6(+) KSHV infection showed a distinct transcriptional profile of elevated IFN-pathway activation with immune suppression and were compromised in T-cell stimulation function compared to those from vIL-6(-) KSHV infection or uninfected control. Notably, a viral nuclear long noncoding RNA (PAN RNA), which is required for sustaining KSHV gene expression, was substantially reduced in infected primary monocytes upon vIL-6(-) KSHV infection. These results highlight the critical role of vIL-6 in sustaining KSHV transcription in primary monocytes. Our findings also imply a clever strategy in which KSHV utilizes vIL-6 to secure its viral pool by expanding infected monocytes via differentiating into longer-lived dysfunctional macrophages. This mechanism may facilitate KSHV to escape from host immune surveillance and to support a lifelong infection.

中文翻译：

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病毒编码的白介素 6 促进 KSHV 在单核细胞中复制并诱导功能失调的巨噬细胞


卡波西肉瘤相关疱疹病毒 (KSHV) 是一种致癌双链 DNA 病毒，也是卡波西肉瘤和高炎症性淋巴增殖性疾病的病原体。了解 KSHV 增加感染细胞数量的机制对于治疗 KSHV 相关疾病至关重要。使用 scRNA-seq，我们证明 KSHV 优先感染 CD14 +单核细胞通过病毒白细胞介素 6 (vIL-6) 维持病毒裂解复制，激活 STAT1 和 3，并诱导炎症基因表达程序。为了研究 vIL-6 在 KSHV 感染后在单核细胞中的作用，我们生成了具有提前终止密码子的重组 KSHV (vIL-6(-)) 及其回复病毒 (vIL-6(+))。重组病毒的感染表明，vIL-6（+）和vIL-6（-）KSHV感染均诱导了难以区分的宿主抗病毒反应，单核细胞中STAT1和3被激活；然而，vIL-6(+)而非vIL-6(-)，KSHV感染促进KSHV感染的单核细胞增殖和分化为巨噬细胞。与vIL-6(-) KSHV感染或未感染对照相比，vIL-6(+) KSHV感染产生的巨噬细胞表现出明显的IFN通路激活升高和免疫抑制的转录特征，并且T细胞刺激功能受到损害。值得注意的是，vIL-6(-) KSHV 感染后，维持 KSHV 基因表达所需的病毒核长非编码 RNA (PAN RNA) 在受感染的原代单核细胞中显着减少。这些结果强调了 vIL-6 在维持原代单核细胞 KSHV 转录中的关键作用。 我们的研究结果还暗示了一种巧妙的策略，即 KSHV 利用 vIL-6 通过分化为寿命较长的功能失调巨噬细胞来扩展受感染的单核细胞，从而确保其病毒库的安全。这种机制可能有助于 KSHV 逃避宿主免疫监视并支持终身感染。