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

参与 KSHV 进入口腔粘膜细胞的病毒和细胞因子

• 批准号: 7484187
• 负责人: TIMOTHY M ROSE
• 金额: $ 40.5万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7484187
• 关键词: AIDS related cancer; Acquired Immunodeficiency Syndrome; Adherent Culture; Affinity Chromatography; Antiviral Agents; Area; B-Lymphocytes; Basal Cell; Binding; Biological; Biological Assay; Biology; Cell Differentiation process; Cell Line; Cell Maintenance; Cells; Cellular Tropism; Clinical Research; Confocal Microscopy; Data; Development; Disease; Endothelial Cells; Endothelium; Environment; Epithelial; Epithelial Cells; Epithelial Receptor Cell; Genetic; Glycoproteins; Goals; HIV; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immunosuppression; In Vitro; Individual; Infection; Integrins; Kaposi Sarcoma; Knock-out; Knowledge; Life Cycle Stages; Liquid substance; Literature; Location; Lymphocyte; Lytic; Lytic Phase; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Modeling; Monkeys; Morphology; Mus; Nature; Neoplasms; Oral; Oral cavity; Oral mucous membrane structure; Oropharyngeal; Pathogenesis; Pathway interactions; Patients; Play; Predisposition; Process; Production; RGD (sequence); Receptor Cell; Recombinants; Research; Research Personnel; Role; Rosa; Saliva; Sampling; Signal Transduction; Simplexvirus; Site; Source; Specificity; Structure; System; Therapeutic immunosuppression; Transplant Recipients; Tropism; Tumor Cell Line; Undifferentiated; Viral; Virion; Virus; Virus Diseases; Virus Replication; bean; cell type; in vitro Model; in vivo; keratinocyte; kidney epithelial cell; latent infection; lytic replication; novel; oral cavity epithelium; oral infection; permissiveness; programs; receptor; receptor binding; research study; response; sarcoma; tissue culture; transmission process; tumor; uptake

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.

Kaposi的肉瘤相关疱疹病毒（KSHV）的感染现在被广泛认为是 Kaposi肉瘤（KS）的发展至关重要，这是一种领先的内皮增殖 艾滋病患者的肿瘤。大多数KS案件是由于组合而发生的 在两种与AIDS相关的病例和移植患者中都可以看出，免疫抑制和KSHV感染。这 在艾滋病毒感染的个体中，KS的初始介绍通常发生在口腔中，口腔参与 大多数发展肿瘤的艾滋病患者。因此，KS是最常见的口腔内恶性肿瘤 在艾滋病毒感染的个体中可见。在HIV共感染的宿主中，KSHV经常在口腔粘膜中携带 该病毒被积极地流入唾液中。口服粘膜液是感染性的唯一来源， 可传播的KSHV直接从迄今已鉴定出的受感染患者中分离出来。 最近的证据表明，经历了KSHV裂解复制的口服上皮角质形成细胞是 体内传染病的主要来源。此外，在潜在感染的角质形成细胞中，KSHV具有 被证明被激活并从潜在状态切换到溶解的复制状态，并产生 传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 口腔环境在传播和发病机理中起着重要作用 KSHV。 尽管有令人信服的证据，但对KSHV发病机理的机理和位置的识别 在艾滋病的口腔粘膜中，患者仍然难以捉摸。大多数KSHV研究都针对细胞 由于KSHV在这些细胞类型中的肿瘤发育中的作用，内皮细胞和淋巴细胞起源的起源。这 项目具有长期目标是阐明口腔环境在生物学中的作用 KSHV的发病机理。我们建议进一步开发一种新的系统，用于研究主要的裂解和潜在 口腔上皮角质形成细胞中的感染。我们还将识别并表征病毒和细胞 这些细胞的KSHV进入和感染涉及的因素。特别是，我们将确定 由口腔上皮细胞产生的KSHV的病毒座包膜，这些细胞负责病毒结合和进入， 并确定这些细胞中介导和感染的细胞受体。这些研究将有助于 我们要对KSHV感染所需的细胞相互作用有更全面的了解 口服上皮，对新抗病毒和抗肿瘤的发展具有重要意义 方法。