Role of HTLV-1 HBZ in viral infection

HTLV-1 HBZ 在病毒感染中的作用

基本信息

批准号：
10493383
负责人：
Isabelle Michele Lemasson
金额：
$ 18.63万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10493383
关键词：
Address Affect Attenuated Biology CD4 Positive T Lymphocytes Cell membrane Cells Clinical Treatment Complex Coupled Data Detection Development Disease E1A-associated p300 protein EP300 gene Endocytosis Endosomes Event Foundations Genes Genetic Transcription Giant Cells Glycoproteins Human T-lymphotropic virus 1 Immune Infection Invaded Location Lysosomes Malignant Neoplasms Mediating Membrane Microtubule-Organizing Center Modification Neuraxis Neurodegenerative Disorders Pathologic Pathway interactions Patients Pharmaceutical Preparations Play Population Process Proteins Recycling Refractory Reporting Retroviridae Risk Role Route Site Sorting - Cell Movement Structure T-Lymphocyte Testing Therapeutic Translations Viral Viral Envelope Proteins Viral Proteins Viral Structural Proteins Virus Virus Assembly Virus Diseases base disorder risk improved in vivo leukemia nervous system disorder novel therapeutics particle prevent receptor receptor binding recruit stem success trafficking transmission process vaccine development viral transmission

项目摘要

Human T-cell Leukemia Virus type 1 (HTLV-1) is a complex retrovirus that primarily infects CD4+ T- cells in vivo. HTLV-1 infection is associated with diverse pathological effects, including a fatal form of leukemia and a progressive neurodegenerative disease. As these diseases have proven refractory to numerous therapeutic approaches, current clinical treatments show limited efficacy. Separately, certain aspects of HTLV- 1 biology have hindered the development of a vaccine. One relatively untested approach that may overcome these obstacles is to inhibit the infectious spread of HTLV-1 within the host's T-cell population as a means of reducing the risk of disease development and viral transmission. Central to the development of novel therapies based on this concept is a thorough understanding of the HTLV-1 infection process. HTLV-1 infection between T-cells requires the infected and target cells to come into direct contact. This event triggers polarization of the microtubule organizing center in the infected cell towards the target cell, allowing the HTLV-1 envelope glycoprotein (Env) and other viral structural proteins to translocate to the cell-cell juncture. While Env is central to infection, mechanisms modulating its intracellular trafficking before and during cell-contact-mediated infection are relatively unclear. We recently discovered that the HTLV-1-encoded transcriptional regulator, HBZ, augments infection. We believe this function stems from effects of HBZ on the expression of certain cellular genes that participate in the infection process. Accordingly, we recently found that HBZ activates MYOF transcription. This cellular gene encodes myoferlin, which functions in membrane sorting and plays an important role in endosomal trafficking. Our preliminary data indicate that HBZ activates myoferlin expression by recruiting the cellular coactivator, p300/CBP, to the MYOF gene. Consistent with HBZ-mediated activation, myoferlin is aberrantly expressed in HTLV-1-infected T-cells. Importantly, reduced expression or functional inhibition of myoferlin in these cells inhibits viral infection and diminishes the level of Env. Based on these preliminary data and data from other studies, we hypothesize that myoferlin promotes the trafficking of Env through an endosomal pathway that favors the availability of Env for viral assembly. Without myoferlin, we hypothesize that Env is routed to lysosomes for degradation. We propose to address these hypotheses in Specific Aim 1 in which we will characterize how myoferlin affects Env trafficking in HTLV-1-infected T-cells. Results from this aim will clarify a regulatory mechanism of Env intracellular trafficking that is central to viral infection. Focusing on HBZ- mediated activation of MYOF transcription, we hypothesize that specific compounds that block the interaction between HBZ and p300/CBP will reduce myoferlin expression and, in turn, viral infection. We propose to test this hypothesis in Specific Aim 2 in which we will identify compounds that block the interaction. For HTLV-1 carriers and patients alike, results from this aim will identify compounds with potential therapeutic capabilities.

人类T细胞白血病1型（HTLV-1）是一种复杂的逆转录病毒，主要在体内感染CD4+ T-细胞。 HTLV-1感染与不同的病理作用有关，包括致命的白血病和进行性神经退行性疾病。由于这些疾病已证明对众多治疗方法的难治性，目前的临床治疗效果有限。另外，HTLV-1生物学的某些方面阻碍了疫苗的开发。一种可能克服这些障碍的相对未经测试的方法是抑制HTLV-1在宿主T细胞种群中的传染性传播，以降低疾病发展和病毒传播的风险。基于此概念的新疗法发展的核心是对HTLV-1感染过程的透彻理解。 T细胞之间的HTLV-1感染要求感染和靶细胞直接接触。该事件触发了感染细胞中微管组织中心向靶细胞的极化，从而使HTLV-1包膜糖蛋白（ENV）和其他病毒结构蛋白可以转移到细胞细胞连接处。虽然ENV是感染的核心，但在细胞接触介导的感染之前和期间调节其细胞内运输的机制相对尚不清楚。我们最近发现，HTLV-1编码的转录调节剂HBZ增强感染。我们认为，该功能源于HBZ对参与感染过程的某些细胞基因表达的影响。因此，我们最近发现HBZ激活了MYOF转录。该细胞基因编码Myoferlin，该基因在膜分类中起作用，在内体运输中起重要作用。我们的初步数据表明，HBZ通过将细胞共激活因子p300/cbp募集到MyOF基因来激活肌曲线表达。与HBZ介导的激活一致，在HTLV-1感染的T细胞中肌链曲线异常表达。重要的是，在这些细胞中肌局部的表达或功能抑制降低会抑制病毒感染并降低ENV水平。基于这些初步数据和其他研究的数据，我们假设Myoferlin通过内体途径促进ENV的贩运，从而有利于ENV可用于病毒组装。如果没有肌曲线，我们假设ENV被路由到溶酶体降解。我们建议在特定目标1中解决这些假设，其中我们将表征Myoferlin如何影响HTLV-1感染的T细胞中的ENV运输。该目标的结果将阐明ENV细胞内贩运的调节机制，这是病毒感染的核心。着重于HBz介导的肌动转录激活，我们假设阻断HBz和P300/CBP之间相互作用的特定化合物将降低肌曲线表达，进而减少病毒感染。我们建议在特定目的2中检验这一假设，其中我们将确定阻止相互作用的化合物。对于HTLV-1携带者和患者，此目标的结果将确定具有潜在治疗能力的化合物。