Does the HSV-1 latency associated transcript (LAT) encode a protein?

HSV-1 潜伏期相关转录本 (LAT) 是否编码蛋白质？

• 批准号: 7459582
• 负责人: CLINTON J JONES
• 金额: $ 18.09万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-05 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459582
• 关键词: Acute; Afferent Neurons; Alzheimer' s Disease; Animal Model; Antibodies; Apoptosis; Blindness; Cells; Code; Cornea; Cultured Cells; Depth; Encephalitis; Environment; Epidemiologic Studies; Eye diseases; Facility Construction Funding Category; Frequencies; Funding; Gene Expression; Goals; Herpesviridae; Herpesvirus 1; Human; Immune Sera; Immunosuppression; Individual; Infection; Initiator Codon; Integration Host Factors; Interferons; Laboratories; Light; Link; Molecular; Mus; Mutate; Nebraska; Neuroblastoma; Neurons; Numbers; Open Reading Frames; Oryctolagus cuniculus; Peptides; Plasmids; Play; Proteins; Reagent; Recurrence; Recurrent disease; Research; Research Personnel; Resource Sharing; Resources; Role; Simplexvirus; Stimulus; Stress; Structure of trigeminal ganglion; Study Section; Testing; Therapeutic immunosuppression; Transcript; Trauma; United States; Viral; Virus; Virus Shedding; Work; base; concept; design; expectation; innovation; mutant; novel; protein expression; reactivation from latency; recombinant virus; viral RNA; virology

DESCRIPTION (provided by applicant): Herpes simplex virus type 1 (HSV-1) is the leading cause of infectious corneal blindness and viral induced encephalitis. HSV induced encephalitis (HSE) leads to a significant number of new cases each year, including 2,000 new cases each year in the United States. Recurrent eye disease and HSE can be induced long after the initial infection because HSV-1 has the potential to establish latency in sensory neurons, and then reactivate from latency. In spite of extensive viral gene expression during acute infection of sensory neurons, many neurons survive and establish latency. External stimuli can induce reactivation from latency resulting in virus shedding, recurrent disease, and spread to uninfected individuals. The only abundant viral RNA expressed during latency is the latency-associated transcript (LAT). LAT inhibits apoptosis in trigeminal ganglia of infected rabbits or cultured cells. The LAT sequences that inhibit apoptosis are also necessary for reactivation from latency. Recent studies demonstrate that an antibody directed against a novel open reading frame located within the first 1.5 Kb of LAT coding sequences recognizes a protein in human neuroblastoma cells or trigeminal ganglia of mice infected with a LAT expressing HSV-1 strain, but not a LAT null mutant. Additional studies presented in this application demonstrate that mutating the start codons in the first 1.5 Kb of LAT coding sequences reduces the ability of this fragment to inhibit apoptosis in cultured neuroblastoma cells. The project investigators hypothesize that expression of LAT encoded proteins plays a role in the latency-reactivation cycle. The long-term goals of the project investigators are to identify virus and host factors that regulate latency. The Specific Aims of this application are the next step in reaching our long-term goals. Studies in Specific Aim 1 will test whether LAT protein coding sequences within the 1.5 Kb LAT fragment are expressed in trigeminal ganglia of infected mice. Studies in Specific Aim 2 will test whether a LAT encoded protein inhibits apoptosis. Studies in Specific Aim 3 will develop recombinant viruses that will not be able to express LAT proteins. The research planned is innovative because it will test whether a protein encoded by LAT plays a role in the latency-reactivation cycle. Completion of these studies will enhance our understanding of how LAT regulates the HSV-1 latency-reactivation cycle. This application will develop antiserum that will recognize proteins encoded by the HSV-1 LAT. Studies will also determine whether LAT encoded proteins inhibit apoptosis, and whether these proteins are necessary for the latency reactivation cycle.

描述(申请人提供)：单纯疱疹病毒1型(HSV-1)是感染性角膜失明和病毒性脑炎的主要原因。单纯疱疹病毒引起的脑炎(HSE)每年导致相当数量的新病例，包括美国每年2,000例新病例。由于HSV-1有可能在感觉神经元中建立潜伏期，然后从潜伏期重新激活，因此在最初感染很长一段时间后，可能会诱发复发的眼病和HSE。尽管在感觉神经元急性感染期间有广泛的病毒基因表达，但许多神经元存活并建立潜伏期。外部刺激可以从潜伏期诱导重新激活，导致病毒脱落、疾病复发，并传播给未感染的人。在潜伏期表达的唯一丰富的病毒RNA是潜伏期相关转录本(LAT)。Lat抑制感染兔或培养细胞的三叉神经节细胞凋亡。抑制细胞凋亡的LAT序列也是从潜伏期重新激活所必需的。最近的研究表明，针对位于LAT编码序列前1.5kb内的新的开放阅读框的抗体可以识别表达HSV-1的LAT株感染的人神经母细胞瘤细胞或小鼠三叉神经节中的蛋白质，但不识别LAT缺失突变体。本申请中提出的其他研究表明，突变前1.5kb的LAT编码序列中的起始密码子会降低该片段抑制培养的神经母细胞瘤细胞凋亡的能力。项目调查人员假设LAT编码蛋白的表达在潜伏期-重新激活周期中发挥作用。该项目调查人员的长期目标是确定控制潜伏期的病毒和宿主因素。这项申请的具体目标是实现我们长期目标的下一步。针对特定目标1的研究将测试1.5kb LAT片段中的LAT蛋白编码序列是否在感染小鼠的三叉神经节中表达。在特定目标2中的研究将测试LAT编码的蛋白质是否抑制细胞凋亡。针对特定目标3的研究将开发出不能表达LAT蛋白的重组病毒。这项计划中的研究具有创新性，因为它将测试LAT编码的蛋白质是否在潜伏期-重新激活周期中发挥作用。这些研究的完成将加深我们对LAT如何调节HSV-1潜伏期-重新激活周期的理解。这一应用将开发识别HSV-1 LAT编码蛋白的抗血清。研究还将确定LAT编码的蛋白质是否抑制细胞凋亡，以及这些蛋白质是否对潜伏期重新激活周期是必要的。