Herpesviral Gene Expression in Kaposis Sarcoma

卡波西肉瘤相关疱疹病毒(KSHV；又称人类疱疹病毒8型)的感染是卡波西肉瘤(KS)发展的关键因素，KS是一种内皮细胞增生性病变，直到最近仍是艾滋病患者最常见的肿瘤。在KS肿瘤中，病毒基因组潜伏在大多数梭形细胞内；较少的肿瘤细胞显示裂解感染。这项资助始于对KS肿瘤中病毒基因表达的检查，确定了在这一背景下表达的几个潜伏基因和裂解基因。本更新申请寻求进一步表征这些基因的表达和功能。具体地说，我们将(I)建立KSHV潜伏期内皮细胞培养模型，并利用它来开发用于创建和分析突变KSHV基因组的遗传系统；(Ii)表征编码ORF71、72和73的主要KSHV潜伏期基因座表达的表型后果；(Iii)进一步探索KSHV K1蛋白构成信号的机制和后果；(Iv)表征KSHV kaposin基因产物的生化活性和相互作用；以及(V)鉴定丰富的病毒核糖核蛋白复合体的成分并确定它们的功能。

Infection by Kaposi's sarcoma-associated herpesvirus (KSHV; also called human herpesvirus 8) is a key factor in the development of Kaposi's sarcoma (KS), a proliferative lesion of endothelial cells that until recently was the commonest neoplasm of AIDS patients. In KS tumors, the viral genome resides within the majority of spindle cells in a latent state; smaller numbers of tumor cells display lytic infection. This grant began with the examination of viral gene expression in KS tumors, identifying several latent and lytic genes expressed in that context. The present renewal application seeks to further characterize the expression and function of these genes. Specifically, we will (i) develop an endothelial cell culture model of KSHV latency and use it to develop a genetic system for the creation and analysis of mutant KSHV genomes; (ii) characterize the phenotypic consequences of expression of a major KSHV latency locus encoding orfs 71,72 and 73; (iii) further explore the mechanisms and consequences of constitutive signaling by the KSHV K1 protein; (iv) characterize the biochemical activities and interactions of the KSHV kaposin gene products; and (v) identify the constituents of an abundant viral ribonucleoprotein complex and determine their function.