HIV-1-dependent HERV-K proteome

HIV-1依赖性HERV-K蛋白质组

• 批准号: 10005650
• 负责人: LUBBERTUS C MULDER
• 金额: $ 27.16万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-25 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005650
• 关键词: Amino Acid Sequence; Anti-HIV Therapy; Antibodies; Antiviral Agents; Antiviral Therapy; Biological Markers; Biology; Bypass; CD4 Positive T Lymphocytes; Cells; Clinical; Complex; Custom; Cytotoxic T-Lymphocytes; Data; Data Analyses; Data Set; Disease; Dominant-Negative Mutation; Elements; Endogenous Retroviruses; Environment; Expression Profiling; Family; Generations; Genetic Transcription; Genome; Goals; HIV; HIV Infections; HIV-1; Health; Human; Human Characteristics; Human Genome; Immune Targeting; Infection; Intervention; Knowledge; Length; Link; Maps; Mass Spectrum Analysis; Mediating; Methods; Molecular; Nuclear Export; Open Reading Frames; Patients; Peptides; Pharmaceutical Preparations; Plant Roots; Potassium; Primary Infection; Production; Proteins; Proteome; RNA; RNA Splicing; Reagent; Reporting; Research; Resolution; Retroelements; Retrovirus Proteins; Role; Source; Structure; Systems Analysis; Testing; Transcript; Translations; Up-Regulation; Work; analytical tool; base; cell type; data integration; data visualization; deep sequencing; exome; experimental study; high reward; high risk; innovation; insight; novel; protein K; protein expression; sequencing platform; single molecule; tool; viral RNA

Abstract During infection, part of the cellular environment rewired by HIV-1 is composed by endogenous retroviruses. Studies that have revealed the HIV mediated increase of HERV-K HML-2 proteins, underscored HERV-K potential as an excellent source of antigenic targets for anti-HIV therapy. We have found that during HIV-1 infection of primary CD4+ T-cells, the high expressing HERV-K HML-2 elements are those that are unable to autonomously produce proteins. This creates a conundrum about which are the elements that are at the root of HIV-1 dependent HERV-K HML-2 protein production and by what mechanism they achieve it. We will investigate the mechanism by which HIV-1 mediates HERV-K HML-2 protein upregulation during infection. Furthermore, the repetitive nature of HERV-K HML-2 family has undermined their study in relation to the effect they have on HIV-1, as conventional analysis systems are often insufficient. By combining HERV-K-specific RNA and protein expression analyses we have devised an approach that not only can accurately establish the HERV-K expression profile of different cell types, but also determines which of those expressed HERV-Ks produces proteins and peptides. The identity of the specific elements responsible for HERV-K HML-2 protein expression is essential to investigate the consequences of their expression on HIV-HERV-K interaction, as small differences in amino acid sequence have been demonstrated to have important repercussions on their function. Taken together, this proposal will contribute to a better understanding of the relation between HIV-1 infection and HERV-K protein production, and provide the tools to assess specific HERV-K HML-2 as potential HIV-1-dependent antigenic targets for antiviral therapy.

摘要 在感染过程中，HIV-1重新连接的部分细胞环境由内源性逆转录病毒组成。 研究显示，HIV介导的HERV-K HML-2蛋白增加，强调HERV-K 作为抗HIV治疗的抗原靶点的极好来源的潜力。我们发现在HIV-1感染期间 感染原代CD 4 + T细胞，高表达HERV-K HML-2元件是那些不能 自主生产蛋白质。这就产生了一个难题，即哪些元素是 HIV-1依赖的HERV-K HML-2蛋白的产生以及它们通过什么机制实现它。 研究HIV-1在感染过程中介导HERV-K HML-2蛋白上调的机制。 此外，HERV-K HML-2家族的重复性破坏了他们关于HERV-K HML-2效应的研究。 他们对HIV-1的分析，因为传统的分析系统往往是不够的。通过结合HERV-K特异性 RNA和蛋白质表达分析，我们设计了一种方法，不仅可以准确地建立 不同细胞类型的HERV-K表达谱，但也决定了哪些表达HERV-Ks 产生蛋白质和肽。HERV-K HML-2蛋白特异性元件的鉴定 表达对于研究其表达对HIV-HERV-K相互作用的后果至关重要， 已经证明氨基酸序列中的微小差异对它们的功能具有重要影响。 功能总之，这一建议将有助于更好地了解艾滋病毒-1之间的关系 感染和HERV-K蛋白的产生，并提供工具来评估特定的HERV-K HML-2作为潜在的 抗病毒治疗的HIV-1依赖性抗原靶点。