Early Events in KSVH Infection of Primary B-cells

描述（由申请人提供）：卡波西肉瘤相关疱疹病毒（KSHV/HHV-8）与许多人类癌症相关，特别是与AIDS相关的卡波西肉瘤（KS）和胸腔积液淋巴瘤（PEL）。已知软腭KS以及身体和四肢的主要受累是与HIV免疫功能低下人群中AIDS发病相关的常见症状。这已成为一种流行病，KS以及胸腔积液淋巴瘤现已被列为发展中国家艾滋病毒感染者死亡的主要原因。KSHV是15年前发现的，主要是在个人调查员的层面上解决的。该申请的重点是汇集宾夕法尼亚大学社区内的3个突出的研究小组，以加入他们的科学专业知识，以解决KSHV介导的肿瘤发生机制。总体目标是研究在原代B细胞感染的早期阶段通过编码抗原控制病毒的机制。在这些早期阶段针对的基本细胞过程将提供新的新信息，以严格要求成功建立潜伏期的病毒。 该计划包括三个科学项目，一个行政核心，一个重组病毒和载体核心和一个ChIP测序核心。科学项目是：1。RBPJk-LANA复合物在早期感染中的作用; 2. KSHV从头感染后复制失败; 3.原代B细胞早期感染过程中KSHV的染色质调节 这些项目的成功将允许建立一个更全面的机制KSHV感染和发病机制的观点，并提供新的线索，为发展战略，以预防和治疗KSHV相关的癌症在艾滋病毒人群。此外，KSHV生物学新信息的积累对于更广泛的疱疹病毒生物学领域至关重要，有助于深入了解与包括EBV在内的其他病毒相关的肿瘤发生机制，从而减少HIV感染、移植和其他免疫功能低下人群的疾病负担

DESCRIPTION (provided by applicant): Kaposi's sarcoma associated herpesvirus (KSHV/HHV-8) is associated with a number of human cancers in particular AIDS associated Kaposi sarcoma (KS) and pleural effusion lymphomas (PELs). KS of the soft palate as well as major involvement of the body and extremities has been known to be a common symptom associated with the onset of AIDS in the HIV immunocompromised population. This has become a pandemic and KS as well as pleural effusion lymphomas are now included as the leading causes of death in the HIV population in developing countries. KSHV was identified 15 years ago and has been tackled mostly on a level of the individual investigator. The focus of this application is to bring together 3 prominent groups of investigators within the University of Pennsylvania community to join their scientific expertise to address the mechanism of KSHV mediated oncogenesis. The overall goal will be to investigate the mechanism of viral control by encoded antigens during the early stages of infection of primary B cells. The fundamental cellular processes targeted during these early stages will provide novel new information as to the strict requirements for successful establishment of latency by the virus. The program consists of three scientific projects, an administrative core, a recombineering virus and vector core and a ChIP sequencing core. The scientific projects are: 1. The Role of the RBPJk-LANA complex during early infection; 2. KSHV abortive replication following de novo infection; 3. Chromatin regulation of KSHV during early infection of primary B-cells. The success of these projects will allow for the establishment of a more comprehensive mechanistic view of KSHV infection and pathogenesis and provide new clues for the development of strategies to prevent and treat KSHV associated cancers in the HIV population. In addition the accumulation of new information on KSHV biology will be critical for the broader area of herpesvirus biology with insights into the mechanism of oncogenesis associated with other viruses including EBV and so reducing the burden of disease in the HIV infected, transplants and other immunocompromised population