Immune evasion mechanisms by a tumor herpesvirus in the oral cavity

摘要 卡波西肉瘤相关疱疹病毒(KSHV)是一种大DNA病毒，它是几种 与艾滋病相关的恶性肿瘤，如卡波西氏肉瘤、原发渗出性淋巴瘤和侵袭性形式的 多中心卡斯特尔曼病。KSHV的裂解复制在KSHV诱导的肿瘤发生和 病毒的传播。最近的研究表明，在口腔上皮细胞复制后，KSHV 可以传播到内皮细胞和B细胞，在那里病毒建立潜伏期，导致持续感染 主人的名字。被感染的口腔上皮细胞也是新病毒颗粒进入唾液的来源， 它是病毒在人群中传播的媒介。尽管口腔在医学和生物学上具有重要意义 KSHV感染，目前尚不清楚病毒和宿主因素在裂解性KSHV的调节中起什么作用 口腔上皮细胞感染。KSHV在人类病毒中是独一无二的，它编码四种病毒干扰素 与细胞内的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，可促进细胞生长和细胞存活。虽然这些VIRF中的许多 功能与vIRFs的细胞质功能有关，vIRFs在基因调控中的核心作用，尤其是 在口腔上皮细胞中，这可能促进溶血性KSHV感染仍然知之甚少。揭示vIRFs的作用 在病毒和细胞基因调控方面，我们已经确定了原始人中每个virf的宿主靶基因。 并揭示了每个vIRF具有高度专门化的功能。此外，我们还进行了一次 从KSHV感染细胞中纯化vIRF1蛋白复合体并发现vIRF1可与 一些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 我们的初步数据，这项建议的目标是(目标1)识别vIRFs的直接靶基因并测试它们的 目的2)研究vIRF1、vIRF1在溶血性KSHV感染中的作用，以及vIRF1、vIRF1在溶血性KSHV感染中的作用 其相关的宿主表观遗传因子对促进KSHV的裂解复制至关重要。因为有很多人 在vIRF1调节的宿主基因中，编码已知在其他病毒感染中去调节的因子，如 我们可以预见，vIRF1在KSHV过程中的表观遗传机制和宿主基因靶点的研究 感染可以为未来新的抗病毒疗法的开发提供新的靶点。

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.