HTLV-1 antagonists of HIV restriction factors

HIV限制因子的HTLV-1拮抗剂

基本信息

批准号：
8466151
负责人：
Viviana A Simon
金额：
$ 25.24万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8466151
关键词：
Agreement Anti-Retroviral Agents Antiviral Agents Bypass CD4 Positive T Lymphocytes Cell Culture Techniques Cells Chronic Complement Cytidine Deaminase Data Dendritic Cells Dose Elements Endogenous Retroviruses Enzymes Exclusion Family Family member Generations Genes Genomics Goals HIV HIV-1 HIV-2 Human Human T-lymphotropic virus 1 Immune response Immune system Immunologic Deficiency Syndromes Indium Infection Interferon Type I Interphase Cell Intervention Knowledge Left Length Life Life Cycle Stages Malignant Neoplasms Mediating Methods Molecular Mutate Myeloid Cells Nucleocapsid Pathogenesis Patients Peptide Hydrolases Peptides Play Population Proteins Proviruses Reporting Resistance development Retroviridae Reverse Transcription Role SIV Specificity Staging Structural Genes Structural Protein Structure Subfamily lentivirinae System T-Lymphocyte Testing Time Variant Viral Virion Virus apolipoprotein B mRNA editing enzyme arm base blocking factor deoxyguanosine triphosphate improved inhibitor/antagonist insight macrophage member monocyte mutant novel overexpression particle polypeptide prevent public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Human T-lymphotropic virus type I (HTLV-1) and Human Immunodeficiency virus type 1 (HIV-1) are the most common retroviruses found in humans. Worldwide 15-20 million people are infected with HTLV-1, while another 30 million live with HIV-1. Both retroviruses mainly infect CD4+ T-lymphocytes, but differ with respect to their ability to infect cell populations essential for the generation of innate immune responses (dendritic cells). If left unchecked, the intrinsic arm of the innate immune system blocks retrovirl replication at a single cell level. As a necessary counterstrategy to these intracellular antiretroviral defenses, retroviruses evolved specific proteins to neutralize these natural inhibitors. In contrast to our growing knowledge of lentiviral antagonists (APOBEC3: Vif; Tetherin/BST2: Vpu, Nef and Env; SAMHD1: Vpx), we know very little about how HTLV-1 overcomes these blocks. HTLV-1 has been circulating successfully in human populations for thousands of years suggesting that it must have evolved efficient strategies to bypass host restriction factors. This proposal aims to determine the identity and the underlying mechanisms allowing HTLV-1 to escape from the lentiviral restriction factors APOBEC3, Tetherin/BST2 and SAMHD1. We showed recently that several cytidine deaminase of the APOBEC3 family potently inhibit HTLV-1. We obtained preliminary evidence suggesting that other mechanisms than the described Nucleocapsid-mediated A3G exclusion from virions are required to counteract HTLV-1 restriction by A3G. We will use wild-type and mutant HTLV-1 variants to determine which structural and non-structural genes are required to antagonize APOBEC3 inhibition (Specific Aim 1). The mode of action will be tested using a combination of virus and cell based approaches. In Specific Aim 2 we will use a similar strategy to probe whether HTLV-1 non-structural or structural proteins antagonize human Tetherin/BST2 or SAMHD1 restriction. Structure function experiments and infections of primary human cells will provide insights into a) the underlying mechanisms and b) the consequences of silencing of these restriction factors. The studies outlined will elucidate how HTLV-1's counter-strategies differ from those employed by lentiviruses and will likely open new avenues for harnessing these intracellular inhibitors for treatment of immunodeficiencies and malignancies.

描述（由申请人提供）：人类T淋巴病毒I型（HTLV-1）和人类免疫缺陷病毒1型（HIV-1）是人类中最常见的逆转录病毒。全球15-2000万人感染了HTLV-1，而另外3000万人则使用HIV-1居住。两种逆转录病毒主要感染CD4+ T淋巴细胞，但在感染对先天免疫反应（树突状细胞）必不可少的细胞群体的能力方面有所不同。如果未检查，先天免疫系统的内在臂将在单个细胞水平上阻止逆行女郎复制。作为这些细胞内抗逆转录病毒防御的必要反应，逆转录病毒进化了特定的蛋白质，以中和这些天然抑制剂。与我们对慢病毒拮抗剂的知识不断增长相反（ApoBec3：vif； tetherin/bst2：vpu，nef和env; samhd1：vpx），我们对HTLV-1如何克服这些块知之甚少。 HTLV-1数千年来已经成功地在人类人群中循环，这表明它必须发展有效的策略以绕过宿主限制因素。该建议旨在确定允许HTLV-1从慢病毒限制因子APOBEC3，Tetherin/BST2和SAMHD1逃脱的身份和潜在机制。我们最近表明，APOBEC3家族的几种胞苷脱氨酶有效抑制HTLV-1。我们获得了初步证据，表明除所述的核素介导的A3G排除在病毒座中以外，还需要其他机制来抵消A3G的HTLV-1限制。我们将使用野生型和突变体HTLV-1变体来确定需要哪些结构和非结构基因来拮抗APOBEC3抑制（特定目标1）。将使用病毒和基于细胞的方法的组合对作用方式进行测试。在特定目标2中，我们将使用类似的策略来探测HTLV-1非结构性或结构蛋白与人Tetherin/BST2或SAMHD1限制的拮抗。原代人类细胞的结构功能实验和感染将提供洞察力a）基本机制和b）沉默这些限制因素的后果。概述的研究将阐明HTLV-1的反战略与慢病毒所采用的研究如何不同，并可能开放新的途径来利用这些细胞内抑制剂来治疗免疫缺陷和恶性肿瘤。