HIV-1 mediated reprogramming of T cell gene expression networks

HIV-1介导的T细胞基因表达网络重编程

• 批准号: 2057720
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2057720
• 关键词: HIV; mediated; reprogramming; cell; gene

Virus infection triggers two fundamental types of cellular response: those that inhibit infection (termed immune responses) and those that promote virus production, persistence and/or dissemination (here called reprogramming). The balance between these opposing forms of response dictates the overall outcome of infection and, ultimately, contributes to the pathogenic consequences for the infected host. To date, little is understood regarding the capacity of the pathogenic retrovirus, HIV-1, to reprogramme infected T lymphocytes, or the consequences of such changes for altering cell function. This project will build upon a substantial body of data where we have demonstrated that HIV-1 reorganises the transcriptional landscape of T lymphocytes within the first few hours of infection. We will employ a multi-disciplinary approach including virology, molecular genetics, biochemistry, high-throughput nucleic acid sequencing, single-cell analytics and bioinformatics to tackle the following key questions. One, what are the virus determinants that drive these RNA expression changes and through which signalling pathways do they operate? Two, what genome-wide alterations in chromatin and epigenetic marks underpin changes in RNA levels, and which steps of RNA biogenesis are regulated? Three, do all cells respond to infection equivalently or is there cell-to-cell variation; and if the latter, what cell-specific signatures underpin the differences? Four, how does reprogramming impact the fate of HIV-1 infection, perhaps by altering virus production or persistence (a form of which is called latency)? Together, insight in these areas will yield new information on the dynamic interplay between HIV-1 and its human host.

病毒感染触发两种基本类型的细胞反应：抑制感染的细胞反应（称为免疫反应）和促进病毒产生、持续和/或传播的细胞反应（这里称为重编程）。这些相反的反应形式之间的平衡决定了感染的总体结果，并最终导致受感染宿主的致病后果。迄今为止，人们对致病性逆转录病毒HIV-1重新编程受感染的T淋巴细胞的能力或这种改变改变细胞功能的后果知之甚少。该项目将建立在大量数据的基础上，我们已经证明HIV-1在感染的最初几个小时内重组了T淋巴细胞的转录景观。我们将采用多学科方法，包括病毒学，分子遗传学，生物化学，高通量核酸测序，单细胞分析和生物信息学，以解决以下关键问题。第一，驱动这些RNA表达变化的病毒决定因素是什么？它们通过哪些信号通路起作用？第二，什么样的染色质和表观遗传标记的全基因组改变支持RNA水平的变化，以及RNA生物合成的哪些步骤受到调节？第三，所有细胞对感染的反应是否相同，或者细胞间是否存在差异;如果是后者，什么细胞特异性特征支撑了差异？第四，重编程是如何影响HIV-1感染的命运的，也许是通过改变病毒的生产或持久性（一种称为潜伏期的形式）？总之，在这些领域的洞察力将产生新的信息之间的动态相互作用的HIV-1和它的人类宿主。