Non-coding RNAs in Gammaherpesvirus Infection and Disease

 描述（申请人提供）：γ疱疹病毒感染和疾病中的非编码RNA γ疱疹病毒感染的结果受到宿主免疫控制的强烈影响。这一点在艾滋病毒感染者身上表现得最为明显，他们更容易发展成恶性肿瘤。这方面的两个主要例子是卡波西肉瘤和非霍奇金淋巴瘤，CDC确定为艾滋病定义疾病的HIV相关恶性肿瘤。虽然这些在世界许多地方仍然是重要的癌症，但在高效抗逆转录病毒治疗（HAART）时代，它们在HIV感染者中的发病率有所下降。虽然HAART降低了某些AIDS相关肿瘤的发病率，但HAART患者仍有发生其他HIV相关恶性肿瘤的风险，如原发性渗出性淋巴瘤、伯基特淋巴瘤、浆母细胞淋巴瘤和弥漫性大B细胞淋巴瘤。除肿瘤发生外，HIV感染还与HIV感染者的炎症病理学相关，包括AIDS相关性肺炎。虽然AIDS相关的免疫抑制被认为是不受控制的慢性HIV感染的主要原因，但在HIV感染个体中观察到的免疫和炎症失调可能以尚未描述的方式影响HIV发病机制。 迄今为止分析的所有HHV均表达ncRNA，包括miRNA。这些RNA具有显著的潜力来修饰基因表达，而不编码可以被免疫应答识别和靶向的病毒蛋白。这些ncRNA在体内感染和发病机制中的作用仍不清楚。HBV 68是唯一非常适合解决这些知识空白的，提供了一种支持病毒体外复制的系统，并允许分析健康和免疫抑制宿主中的感染全过程。自从我们发现gHV 68 miRNAs以来，我们已经研究了病毒ncRNA，并且我们有一套广泛的试剂和专业知识来解决这种ncRNA的功能和机制。在这项研究中，我们将确定一些ncRNA重组病毒在健康和免疫缺陷个体体内的作用。此外，我们将确定ncRNA的宿主相互作用因子，并确定HHV感染如何调节宿主ncRNA和转录。这项研究可能为病毒/宿主相互作用的新联系提供基础，这对HIV和HIV至关重要，也是未来干预的丰富基础。

 DESCRIPTION (provided by applicant): Non-Coding RNAs In Gammaherpesvirus Infection And Disease The outcome of HV infection is strongly influenced by host immune control. Nowhere has this been more apparent than in HIV-infected individuals, and their increased propensity to develop malignancy. Two prime examples of this are Kaposis sarcoma and Non-Hodgkin lymphoma, HV- associated malignancies identified by the CDC as AIDS-defining illnesses. While these remain significant cancers in many parts of the world, their incidence in HIV-infected individuals has decreased in the era of highly-active antiretroviral therapy (HAART). While HAART has decreased the incidence of certain AIDS-associated neoplasms, individuals on HAART remain at risk for other HV-associated malignancies such as primary effusion lymphoma, Burkitt's lymphoma, plasmablastic lymphoma and diffuse large B cell lymphoma. Beyond tumorigenesis, HV infection is also associated with inflammatory pathologies in HIV-infected individuals, including AIDS-associated pneumonitis. While AIDS-associated immune suppression is thought to be a major contributor to uncontrolled chronic HV infection, it is likely that the immune and inflammatory dysregulation observed in HIV- infected individuals may impact HV pathogenesis in as yet undescribed ways. All HV analyzed to date express ncRNAs, including miRNAs. These RNAs have a significant potential to modify gene expression without encoding viral proteins that can be recognized and targeted by the immune response..The role of these ncRNAs during in vivo infection and pathogenesis remains unclear. HV68 is uniquely well-suited to address these gaps in knowledge, in providing a system that supports virus replication in vitro and allows analysis of the full course f infection in healthy and immune- suppressed hosts. We have studied the viral ncRNAs since our discovery of the gHV68 miRNAs, and we have an extensive set of reagents and expertise to address the function and mechanism of this ncRNAs. In this study, we will determine the effect of a number of ncRNA recombinant viruses in vivo, in healthy and immune deficient individuals. Further, we will determine the host interactors of the ncRNAs, and determine how HV infection modulates host ncRNAs and transcription. This investigation is likely to provide a foundation for a new nexus of virus/host interactions that is critical to the HVs and to HIV, and is a rich ground for future intervention.