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（由适用提供）：灵长类动病毒均为VIF蛋白进行编码，该蛋白已被证明与载脂蛋白mRNA的成员相互作用，催化多肽样3（Apobec3）蛋白质的超家族。 APOBEC3蛋白是胞苷死亡蛋白，被认为在先天抗病毒限制中起着重要作用。人类和猕猴都为七个APOBEC3基因（A3A，A3B，A3C，A3D，A3F，A3F，A3G和A3H）编码。可以将APOBEC3蛋白广泛分为单个脱氨酸酶结构域（A3A，A3C和A3H）和双脱氨酶域蛋白（A3B，A3D，A3F和A3G）。胸腺对CD4+ T细胞稳态至关重要，并且是幼稚CD4+ T细胞的主要来源。人类的HIV-1感染会导致抑制未成熟胸腺细胞的增殖和/或可以直接感染CD4+胸腺细胞，从而导致CD4+ T细胞的产生受损。这，生产和外周CD4+ T细胞破坏之间的失衡可能会导致它们随着时间的流逝而逐渐下降，并最终导致艾滋病。胸腺在严重依赖胸腺产生新CD4+ T细胞的小儿患者中尤其重要。迄今为止，尚无有关A3基因/蛋白在发育中的胸腺细胞中表达的信息。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，但在人类胸腺的单个阳性（SP CD4+）细胞中表达。这表明该重要病毒限制因子的表达可能受到调节。在特定目标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，确定胸腺细胞发育的阶段。在特定目标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A3基因表达的已知诱导剂是否会刺激表达。拟议的研究将提供有关在发育过程中A3基因表达，胸腺中的病毒持续性以及针对VIF/A3相互作用的抗病毒药的开发的新洞察力。