HIV-1 mediated reprogramming of T cell gene expression networks

病毒感染引发两种基本类型的细胞反应：一种是抑制感染（称为免疫反应），另一种是促进病毒产生、持续和/或传播（这里称为重编程）。这些相反形式的反应之间的平衡决定了感染的总体结果，并最终有助于对受感染宿主的致病后果。迄今为止，关于致病性逆转录病毒HIV-1重新编程感染T淋巴细胞的能力，或这种改变对改变细胞功能的后果，人们知之甚少。这个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。我们将采用多学科的方法，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来解决以下关键问题。第一，驱动这些RNA表达变化的病毒决定因子是什么它们通过哪些信号传导途径起作用？第二，染色质和表观遗传标记的哪些全基因组改变支持RNA水平的变化，以及RNA生物发生的哪些步骤受到调节？第三，是否所有细胞对感染的反应都是一样的，还是存在细胞间的差异；如果是后者，是什么细胞特异性特征支撑了这种差异？第四，重编程如何影响HIV-1感染的命运，可能是通过改变病毒的产生或持续存在（一种形式被称为潜伏期）？总之，在这些领域的洞察将产生关于HIV-1与其人类宿主之间动态相互作用的新信息。

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.