The role of APOBEC3 proteins in innate immune responses in developing thymocytes

APOBEC3 蛋白在胸腺细胞发育中先天免疫反应中的作用

• 批准号: 9065291
• 负责人: Edward Brice Stephens
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9065291
• 关键词: APOCEC3G gene; Acquired Immunodeficiency Syndrome; Antiviral Agents; Apolipoproteins; Apolipoproteins B; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cullin 5 Protein; Cytidine Deaminase; Data; Deaminase; Development; Drug Targeting; Family member; Flow Cytometry; Gene Expression; Gene Proteins; Generations; Genes; HIV; HIV-1; Homeostasis; Human; Immune response; Individual; Infection; Interferon-alpha; Investigation; Knowledge; Laboratories; Lead; Life; Macaca; Macaca mulatta; Messenger RNA; Mutation; Output; Peptides; Peripheral; Play; Population; Primate Lentiviruses; Production; Protein Family; Proteins; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; SIV; Site; Sorting - Cell Movement; Source; Staging; System; T-Cell Development; T-Lymphocyte; Tertiary Protein Structure; Tetanus Helper Peptide; Thymocyte Development; Thymus Gland; Time; Tissues; Viral; Viral Load result; Viral Proteins; Virus; Virus Replication; base; cytokine; elongin C; in vivo; inhibitor/antagonist; insight; member; novel; novel therapeutics; pediatric patients; polypeptide; protein expression; public health relevance; simian human immunodeficiency virus; thymocyte

 DESCRIPTION (provided by applicant): The primate lentiviruses all encode for a Vif protein that has been shown to interact with members of the apolipoprotein mRNA-editing, catalytic polypeptide-like 3 (APOBEC3) superfamily of proteins. The APOBEC3 proteins are cytidine deaminases that are thought to play an important role in innate anti-viral restriction. Humans and macaques both encode for seven APOBEC3 genes (A3A, A3B, A3C, A3D, A3F, A3G, and A3H). The APOBEC3 proteins can be broadly divided into the single deaminase domain (A3A, A3C, and A3H) and double deaminase domain proteins (A3B, A3D, A3F, and A3G). The thymus is essential to CD4+ T cell homeostasis and is the major source of naïve CD4+ T cells throughout life. HIV-1 infection of humans can lead to the inhibition of proliferation of immature thymocytes and/or can directly infect CD4+ thymocytes leading to impaired production of CD4+ T cells. Thus, an imbalance between production and destruction of peripheral CD4+ T cells likely leads to their progressive decline over time and eventually to AIDS. The thymus is particularly important in pediatric patients who depend heavily on their thymus for generation of new CD4+ T cells. To date no information is available on the expression of the A3 genes/proteins in cells of the developing thymus. We present preliminary data that indicate that A3G/A3F proteins are not expressed in the double negative (DN: CD4-CD8-) or double positive (DP:CD4+CD8+) thymocytes but are expressed in single positive (SP CD4+) cells of the human thymus. This indicates that the expression of this important virus restriction factor is likely developmentally regulated. In Specific Aim 1, we propose to perform a comprehensive examination to determine the stage of thymocyte development when A3G/F gene (and other A3 genes) expression becomes activated. In Specific Aim 2, we propose to determine if the stage of A3 gene expression correlates with the ability to restrict HIV-1 and HIV∆vif viruses and determine if known inducers of A3 gene expression will stimulate expression. The proposed studies will provide novel insight into the expression of A3 genes during development, viral persistence in the thymus, and in the development of antiviral drugs targeting Vif/A3 interactions.

 描述（由申请人提供）：灵长类慢病毒均编码 Vif 蛋白，该蛋白已被证明与载脂蛋白 mRNA 编辑催化多肽样 3 (APOBEC3) 蛋白超家族的成员相互作用。 APOBEC3 蛋白是胞苷脱氨酶，被认为在先天抗病毒限制中发挥重要作用。人类和猕猴均编码七个 APOBEC3 基因（A3A、A3B、A3C、A3D、A3F、A3G 和 A3H）。 APOBEC3 蛋白可大致分为单脱氨酶结构域（A3A、A3C 和 A3H）和双脱氨酶结构域蛋白（A3B、A3D、A3F 和 A3G）。胸腺对于 CD4+ T 细胞稳态至关重要，并且是一生中幼稚 CD4+ T 细胞的主要来源。人类的 HIV-1 感染可导致未成熟胸腺细胞增殖受到抑制和/或可直接感染 CD4+ 胸腺细胞，导致 CD4+ T 细胞的产生受损。因此，外周 CD4+ T 细胞的产生和破坏之间的不平衡可能导致其随着时间的推移逐渐衰退，并最终导致艾滋病。胸腺对于儿科患者尤为重要，因为他们严重依赖胸腺来生成新的 CD4+ T 细胞。迄今为止，尚无关于发育中胸腺细胞中 A3 基因/蛋白质表达的信息。我们提供的初步数据表明，A3G/A3F 蛋白不在双阴性（DN：CD4-CD8-）或双阳性（DP：CD4+CD8+）胸腺细胞中表达，但在人胸腺的单阳性（SP CD4+）细胞中表达。这表明这种重要的病毒限制因子的表达可能受到发育调节。在具体目标1中，我们建议进行全面检查，以确定当A3G/F基因（和其他A3基因）表达被激活时胸腺细胞的发育阶段。在具体目标 2 中，我们建议确定 A3 基因表达的阶段是否与限制 HIV-1 和 HIVΔvif 病毒的能力相关，并确定已知的 A3 基因表达诱导剂是否会刺激表达。拟议的研究将为发育过程中 A3 基因的表达、病毒在胸腺中的持久性以及针对 Vif/A3 相互作用的抗病毒药物的开发提供新的见解。