HTLV-1 antagonists of HIV restriction factors

HIV限制因子的HTLV-1拮抗剂

• 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
• 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

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（由申请方提供）：人类嗜T淋巴细胞病毒I型（HTLV-1）和人类免疫缺陷病毒I型（HIV-1）是人类中最常见的逆转录病毒。全世界有1500万至2000万人感染HTLV-1，另有3000万人感染HIV-1。这两种逆转录病毒主要感染CD 4 + T淋巴细胞，但在感染先天免疫应答产生所必需的细胞群（树突细胞）的能力方面有所不同。如果不加以检查，先天免疫系统的内在臂在单细胞水平上阻断逆转录病毒复制。作为这些细胞内抗逆转录病毒防御的必要对抗策略，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（APOBEC 3：Vif; Tetherin/BST 2：Vpu，Nef和Env; SAMHD 1：Vpx）的了解不断增加相反，我们对HTLV-1如何克服这些障碍知之甚少。HTLV-1已经在人群中成功传播了数千年，这表明它必须进化出有效的策略来绕过宿主限制因子。 该提案旨在确定HTLV-1从慢病毒限制因子APOBEC 3，Tetherin/BST 2和SAMHD 1中逃逸的身份和潜在机制。我们最近发现APOBEC 3家族的几种胞苷脱氨酶有效抑制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A3 G从病毒体中排除之外，还需要其他机制来抵消A3 G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APOBEC 3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的组合来测试作用模式。在具体目标2中，我们将使用类似的策略来探测HTLV-1非结构或结构蛋白是否拮抗人Tetherin/BST 2或SAMHD 1限制。原代人类细胞的结构功能实验和感染将提供对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的途径。