Non-coding RNAs in Gammaherpesvirus Infection and Disease

伽马疱疹病毒感染和疾病中的非编码 RNA

• 批准号: 9263885
• 负责人: Linda F. Van Dyk
• 金额: $ 38.54万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-19 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9263885
• 关键词: AIDS related cancer; Acquired Immunodeficiency Syndrome; Acute; Address; Animal Model; Binding; Burkitt Lymphoma; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; DNA Polymerase III; Defect; Disease; Disease Outcome; Disease model; Elements; Equilibrium; Foundations; Frequencies; Future; Gap Junctions; Gene Expression; Genetic; Genetic Transcription; Goals; HIV; HIV Infections; Herpesviridae; Highly Active Antiretroviral Therapy; Human; Human Herpesvirus 4; Human Herpesvirus 8; Hybrids; Immune; Immune Targeting; Immune response; Immunity; Immunosuppression; In Vitro; Incidence; Individual; Infection; Inflammatory; Intervention; Investigation; Kaposi Sarcoma; Knowledge; Large-Cell Immunoblastic Lymphoma; Link; Lysine-Specific tRNA; Malignant Neoplasms; Mediating; Methods; MicroRNAs; Mus; Nature; Neoplasms; Non-Hodgkin' s Lymphoma; Nucleic Acids; Pathogenesis; Pathology; Patients; Pneumonia; Process; Protein Biosynthesis; Proteins; Pulmonary Inflammation; RNA; RNA Polymerase III; RNA-Binding Proteins; Reagent; Regulation; Research Proposals; Risk; Role; Species Specificity; Specificity; Support System; System; Testing; Transfer RNA; Untranslated RNA; Viral; Viral Proteins; Virion; Virus; Virus Diseases; Virus Replication; base; cytokine; gammaherpesvirus; in vivo; interest; large cell Diffuse non-Hodgkin' s lymphoma; mutant; patient population; primary effusion lymphoma; public health relevance; recombinant virus; response; sarcoma; sensor; tripolyphosphate; tumorigenesis; virus host interaction

 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.

 描述(申请人提供)：非编码RNA在伽马疱疹病毒感染和疾病中的作用HV感染的结局受到宿主免疫控制的强烈影响。这一点在感染艾滋病毒的人身上表现得最为明显，他们发展为恶性肿瘤的倾向也增加了。两个主要的例子是卡波西斯肉瘤和非霍奇金淋巴瘤，HV相关的恶性肿瘤被疾控中心确定为艾滋病定义的疾病。虽然这些癌症在世界许多地区仍然是重要的癌症，但在高效抗逆转录病毒疗法(HAART)的时代，它们在艾滋病毒感染者中的发病率已经下降。虽然抗逆转录病毒疗法降低了某些艾滋病相关肿瘤的发病率，但服用抗逆转录病毒疗法的患者仍有患其他HV相关恶性肿瘤的风险，如原发渗出性淋巴瘤、伯基特淋巴瘤、浆母细胞淋巴瘤和弥漫性大B细胞淋巴瘤。除了肿瘤发生，HV感染还与艾滋病毒感染者的炎性病理有关，包括艾滋病相关性肺炎。虽然艾滋病相关的免疫抑制被认为是导致慢性HV感染失控的主要原因，但在HIV感染者身上观察到的免疫和炎症失调可能以尚未描述的方式影响HV的发病。到目前为止，所有分析的HV都表达ncRNA，包括miRNAs。这些RNA有很大的潜力来改变基因的表达，而不是编码可以被免疫反应识别和靶向的病毒蛋白。这些ncRNAs在体内感染和发病机制中的作用尚不清楚。Hv68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的感染全程，是唯一非常适合解决这些知识差距的产品。自从我们发现gHV68 miRNAs以来，我们已经对病毒ncRNAs进行了研究，我们有一套广泛的试剂和专业知识来研究这种ncRNAs的功能和机制。在这项研究中，我们将确定一些ncRNA重组病毒在体内的效果，在健康和免疫缺陷的个人。此外，我们将确定ncRNAs的宿主相互作用因子，并确定HV感染如何调节宿主ncRNAs和转录。这项调查很可能为病毒/宿主相互作用的新联系提供基础，这种联系对HV和艾滋病毒至关重要，并为未来的干预提供了丰富的基础。