Immune evasion mechanisms by a tumor herpesvirus in the oral cavity

摘要 卡波济肉瘤相关疱疹病毒（Kaposi's sarcoma-associated herpesvirus，KSHV）是一种大DNA病毒， 艾滋病相关的恶性肿瘤，如卡波西肉瘤，原发性渗出性淋巴瘤，以及侵袭性形式的 多中心Castleman病KSHV的裂解性复制对于KSHV诱导的肿瘤发生和细胞增殖都是至关重要的。 病毒的传播。最近的研究表明，KSHV在口腔上皮细胞中复制后， 可传播到内皮细胞和B细胞，在那里病毒建立潜伏期，导致持续感染 的主机。受感染的口腔上皮细胞也是新病毒颗粒脱落到唾液中的来源， 介导病毒在人群中的传播。尽管口腔医学和生物学的重要性 KSHV感染后，病毒和宿主因子在KSHV裂解的调节中起作用仍是未知的 口腔上皮细胞感染。KSHV在人类病毒中是独特的，它编码四种病毒干扰素 与细胞IRF同源的调节因子。这些病毒蛋白已被证明可以调节许多 不同的免疫相关途径，并能增强细胞生长和细胞存活。虽然许多这些vIRF 功能与vIRFs的细胞质功能、vIRFs在基因调控中的核作用，特别是 在口腔上皮细胞中，可能促进溶解性KSHV感染的机制仍然知之甚少。为了揭示vIRFs的作用， 在病毒和细胞基因调控方面，我们已经在原代人中鉴定了每个vIRF的宿主靶基因， 牙龈上皮细胞，并揭示了每个vIRF高度专业化的功能。此外，我们还执行了一项 从KSHV感染的细胞中纯化vIRF 1的蛋白复合物，并发现vIRF 1可以与 几种宿主表观遗传因子参与DNA结合、组蛋白乙酰化或组蛋白甲基化。基于 根据我们的初步数据，本提案的目标是（目的1）鉴定vIRFs的直接靶基因，并测试其 目的2：探讨vIRF 1和vIRF 2介导的基因调控机制， 其相关的宿主表观遗传因子，这对于促进KSHV的裂解复制至关重要。由于许多 的vIRF 1调节的宿主基因编码已知在其他病毒感染中被解除调节的因子， 因此，我们认为，对KSHV过程中vIRF 1的表观遗传机制和宿主基因靶点的研究， 感染可以为未来开发新的抗病毒疗法提供新的靶点。

Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV) is large DNA virus, which is the etiological agent of several AIDS-related malignancies such as Kaposi’s sarcoma, primary effusion lymphoma, and aggressive forms of multicentric Castleman’s disease. Lytic replication of KSHV is critical for both KSHV-induced tumorigenesis and dissemination of the virus. Recent studies have shown that following replication in the oral epithelial cells, KSHV can be transmitted into endothelial and B cells where the virus establishes latency resulting persistent infection of the host. Infected oral epithelial cells also serve as the source of new viral particles shedding into the saliva, which mediates the viral transmission in the population. Despite the medical and biological importance of oral KSHV infection, it is still largely unknown what viral and host factors play a role in the regulation of lytic KSHV infection of oral epithelial cells. KSHV is unique among human viruses that it encodes four viral interferon regulatory factors that are homologous to cellular IRFs. These viral proteins have been shown to regulate many different immune-related pathways and can enhance cell growth and cell survival. While many of these vIRF functions are linked to the cytoplasmic functions of vIRFs, the nuclear role of vIRFs in gene regulation, especially in oral epithelial cells, that may promote lytic KSHV infection is still poorly understood. To reveal the role of vIRFs in viral and cellular gene regulation, we have identified the host target genes of each vIRF in primary human gingival epithelial cells and revealed a highly specialized function for each vIRF. In addition, we performed a protein complex purification of vIRF1 from KSHV-infected cells and discovered that vIRF1 can interact with several host epigenetic factors involved in DNA binding, histone acetylation or histone methylation. Based on our preliminary data, the goal of this proposal is (Aim 1) to identify the direct target genes of vIRFs and test their role in lytic KSHV infection, and (Aim 2) to investigate the gene regulatory mechanisms mediated by vIRF1 and its associated host epigenetic factors, which can be critical for facilitating lytic replication of KSHV. Since many of the vIRF1-regulated host genes encode factors that are known to be de-regulated in other viral infections as well, we envision that the investigation of epigenetic mechanisms and host gene targets of vIRF1 during KSHV infection can provide novel targets for future development of new antiviral therapies.