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）：I 型人类 T 淋巴细胞病毒 (HTLV-1) 和 1 型人类免疫缺陷病毒 (HIV-1) 是人类中最常见的逆转录病毒。全球有 15-2000 万人感染 HTLV-1，另有 3000 万人感染 HIV-1。两种逆转录病毒主要感染 CD4+ T 淋巴细胞，但感染产生先天免疫反应所必需的细胞群（树突状细胞）的能力有所不同。如果不加以控制，先天免疫系统的固有臂会在单细胞水平上阻止逆转录病毒的复制。作为这些细胞内抗逆转录病毒防御的必要对策，逆转录病毒进化出特定的蛋白质来中和这些天然抑制剂。与我们对慢病毒拮抗剂（APOBEC3：Vif；Tetherin/BST2：Vpu、Nef 和 Env；SAMHD1：Vpx）的了解不断增长相反，我们对 HTLV-1 如何克服这些阻断知之甚少。 HTLV-1 已在人群中成功传播了数千年，这表明它一定已经进化出有效的策略来绕过宿主限制因素。该提案旨在确定 HTLV-1 逃离慢病毒限制因子 APOBEC3、Tetherin/BST2 和 SAMHD1 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可有效抑制 HTLV-1。我们获得的初步证据表明，除了所描述的核衣壳介导的 A3G 从病毒粒子中排除之外，还需要其他机制来抵消 A3G 对 HTLV-1 的限制。我们将使用野生型和突变型 HTLV-1 变体来确定拮抗 APOBEC3 抑制所需的结构和非结构基因（具体目标 1）。将使用基于病毒和细胞的方法相结合来测试作用模式。在具体目标 2 中，我们将使用类似的策略来探讨 HTLV-1 非结构蛋白或结构蛋白是否拮抗人 Tetherin/BST2 或 SAMHD1 限制。结构功能实验和原代人类细胞的感染将提供对a）潜在机制和b）这些限制因子沉默的后果的见解。概述的研究将阐明 HTLV-1 的对抗策略与慢病毒所采用的策略有何不同，并可能为利用这些细胞内抑制剂治疗免疫缺陷和恶性肿瘤开辟新途径。