Inhibitory targeting of HHV-8 vIL-6-related interactions.

描述（由申请人提供）：人类疱疹病毒8 （HHV-8）指定白细胞介素6 （vIL-6）的同源物，该同源物与HHV-8相关的卡波西肉瘤、原发性积液性淋巴瘤（PEL）和多中心Castleman病（MCD）的发生和进展有关。我们已经确定，在PEL细胞中，vIL-6在潜伏期以低但功能水平表达；在这种情况下，il -6支持细胞生长和存活，以及这些功能

DESCRIPTION (provided by applicant): Human herpesvirus 8 (HHV-8) specifies a homologue of interleukin-6, vIL-6, which is implicated in the development and progression of HHV-8-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). We have determined that in PEL cells vIL-6 is expressed at low but functional levels during latency; vIL-6 in this setting supports cell growth and survival, and these functions are mediated predominantly intracellularly by vIL-6 localized in the endoplasmic reticulum (ER). Thus, intracrine, strictly autocrine signaling by vIL-6 is likely to be an important contributor to PEL disease and represents a unique mode of cytokine activity in disease pathogenesis. The mechanisms underlying this activity of vIL-6 in PEL cells is not understood, but we have identified a functionally important interaction of vIL-6 with a novel protein, vitamin K epoxide reductase complex subunit 1 variant-2 (VKORC1v2), and also have recently determined that the IL-6 signal transducer, gp130, is essential for sustained growth of PEL cells. Additionally, we have identified interactions of VKORC1v2 with thioredoxin reductase-like protein 1 (TMX1), protein disulfide isomerase A6/P5 (PDI-A6) and cathepsin D (catD) that suggest possible functions of VKORC1v2 related to vIL-6 folding and/or influence of vIL-6, via VKORC1v2 interaction, on ER stress responses or on catD processing and associated regulation of pro-proliferative and apoptotic signaling. In this R21 application, we propose to identify and test in respect of PEL inhibition peptide and small molecule inhibitors of vIL- 6:VKORC1v2 interaction and functional vIL-6:gp130 complexing; we will also assess the effects of validated inhibitors on functions predicted from interaction of VKORC1v2 with its newly identified cellular interaction partners. The work therefore extends our functional characterization of vIL-6 interactions with VKORC1v2 and gp130 in the context of PEL and addresses molecular strategies to target these biologically important virus- host interactions. The project has substantial significance to the future development of drug-based therapies for this and possibly other HHV-8-associated malignancies in which vIL-6 is likely to play a critical role.