Viral and cellular factors involved in KSHV entry in cells of the oral mucosa

卡波西肉瘤相关疱疹病毒（KSHV）感染现在被广泛认为是 对于卡波西肉瘤（KS）的发展至关重要， 艾滋病患者的肿瘤。大多数KS病例的发生是以下因素结合的结果： 免疫抑制和KSHV感染，如在艾滋病相关病例和移植患者中所见。的 在HIV感染者中，KS的最初表现通常发生在口腔中， 大多数艾滋病患者都发展成肿瘤。因此，KS是最常见的口腔内恶性肿瘤 在HIV感染者中发现。在HIV共感染的宿主中，KSHV经常在口腔粘膜中携带 病毒会主动进入唾液口腔粘膜液是唯一的传染源， 迄今为止，从已被确定的感染患者中直接分离的可传播的KSHV。 最近的证据表明，经历KSHV裂解性复制的口腔上皮角质形成细胞， 体内感染性病毒的主要来源。此外，在潜伏感染的角质形成细胞中，KSHV具有 被激活并从潜伏状态转换到裂解复制状态， 感染性病毒，因为角质形成细胞经历其正常的分化途径。这些研究表明 口腔环境在口腔溃疡的传播和发病中起着重要的作用， KSHV 尽管有令人信服的证据，但KSHV发病机制和发病部位的鉴定 在艾滋病患者的口腔粘膜中仍然是难以捉摸的。大多数KSHV研究都是针对细胞的， 由于KSHV在这些细胞类型的肿瘤发展中的作用，这 该项目的长期目标是阐明口腔环境在生物学中的作用， KSHV的发病机制我们建议进一步开发一种新的系统，用于研究原发性溶解性和潜伏性 口腔上皮角化细胞感染。我们还将识别和表征病毒和细胞 KSHV进入和感染这些细胞的因素。特别是，我们将确定的成分 由口腔上皮细胞产生的KSHV的病毒体包膜负责病毒结合和进入， 并确定这些细胞中介导侵入和感染的细胞受体。这些研究将有助于 我们开发一个更完整的理解KSHV感染的细胞所需的相互作用， 口腔上皮与新的抗病毒和抗肿瘤药物的开发有着重要的意义 接近。

Infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is now widely acknowledged to be essential for the development of Kaposi's sarcoma (KS), an endothelial proliferation that is the leading neoplasm of AIDS patients. The majority of KS cases occur as a consequence of the combination of immunosuppression and KSHV infection, as seen in both AIDS-related cases and in transplant patients. The initial presentation of KS in HIV-infected individuals often occurs in the mouth, with oral cavity involvement in the majority of AIDS patients who develop the neoplasm. Thus, KS is the most common intraoral malignancy seen in HIV-infected individuals. In the HIV co-infected host, KSHV is frequently carried in the oral mucosa and the virus is actively shed into the saliva. The oral mucosal fluid is the only source of infectious, transmissible KSHV isolated directly from infected patients that has been identified to date. Recent evidence suggests that oral epithelial keratinocytes undergoing lytic replication of KSHV are the primary source of infectious virus in vivo. Furthermore, in latently-infected keratinocytes, KSHV has been shown to be activated and switch from a latent state to a lytically replicating state with production of infectious virus as the keratinocytes undergo their normal pathway of differentiation. These studies suggest that the environment of the oral cavity plays an important role in the transmission and pathogenesis of KSHV. Despite compelling evidence, identification of the mechanism and the location of KSHV pathogenesis in the oral mucosa of AIDS patients has remained elusive. The majority of KSHV research has targeted cells of endothelial and lymphocyte origin, due to the role of KSHV in tumor development in these cell types. This project has as a long term goal the elucidation of the role of the oral environment in the biology and pathogenesis of KSHV. We propose to further develop a novel system for studying primary lytic and latent infections in the oral epithelial keratinocytes. We will also identify and characterize the viral and cellular factors involved in KSHV entry and infection of these cells. In particular, we will identify the constituents of the virion envelope of KSHV produced by oral epithelial cells that are responsible for virus binding and entry, and determine the cellular receptors in these cells that mediate entry and infection. These studies will help us to develop a more complete understanding of the cellular interactions required for KSHV infection of the oral epithelium with important implications regarding the development of new antiviral and anti-tumor approaches.