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)的感染现在被广泛承认是 对于Kaposi肉瘤(KS)的发展是必不可少的，KS是一种主要的内皮细胞增殖 艾滋病患者的肿瘤。大多数KS病例的发生是由于 免疫抑制和KSHV感染，在艾滋病相关病例和移植患者中都可以看到。这个 HIV感染者的KS最初通常发生在口腔，口腔受累 大多数艾滋病患者患上了肿瘤。因此，KS是最常见的口腔内恶性肿瘤。 见于感染艾滋病毒的人。在HIV混合感染的宿主中，KSHV经常在口腔粘膜中携带 病毒被活跃地排入唾液中。口腔粘膜液是感染性的唯一来源， 迄今已被确认的直接从感染患者中分离到的可传播KSHV。 最近的证据表明，口腔上皮角质形成细胞在KSHV裂解复制过程中 体内传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 已经被证明是激活的，并随着产生 感染性病毒作为角质形成细胞经历其正常的分化途径。这些研究表明 口腔环境在口腔炎的传播和发病机制中起重要作用 KSHV。 尽管有令人信服的证据，但对KSHV致病机制和位置的鉴定 在艾滋病患者的口腔粘膜中仍然难以捉摸。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，KSHV在内皮细胞和淋巴细胞性来源中的作用。这 该项目的长期目标是阐明口腔环境在生物和环境中的作用 KSHV的致病机理。我们建议进一步开发一种研究原生裂解和潜伏裂解的新系统 口腔上皮角质形成细胞的感染。我们还将识别和表征病毒和细胞 参与KSHV进入和感染这些细胞的因素。特别是，我们将确定 KSHV的病毒粒子被膜由负责病毒结合和进入的口腔上皮细胞产生， 并确定这些细胞中介导进入和感染的细胞受体。这些研究将会有所帮助 美国将更全面地了解感染KSHV所需的细胞相互作用 口腔上皮细胞对新型抗病毒和抗肿瘤药物开发的重要意义 接近了。

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.