Type 1 interferon resistance in the HIV-1 envelope glycoprotein

HIV-1在个体之间传播的一个关键因素是该病毒对1型干扰素(干扰素-I)的抗病毒活性具有内在的抵抗力。6个月后，传播的病毒对干扰素-I的抵抗力高于从受体伴侣分离的病毒。干扰素-I对HIV-1复制的影响是由干扰素诱导基因(ISGs)介导的，其中几个基因直接抑制病毒生命周期的各个阶段。干扰素诱导的跨膜蛋白(IFITM)是广泛作用的ISGs，其靶向是由其包膜糖蛋白(Env)介导的细胞进入过程。我们已经发现，传播的HIV-1毒株对IFITM具有耐药性，但随着Env适应逃避宿主抗体反应，敏感性随着时间的推移而增加。对IFITMS不敏感在很大程度上导致了传播病毒对干扰素-I的抵抗力。初步数据表明，Env对IFITM/干扰素的耐药性与其与其受体CD4结合时必须经历的结构重排有关。环境越稳定，对IFITM的抵抗力越强。因此，传播的包膜病毒在结构上受到干扰素抗药性的需要的限制。由于这是有效疫苗需要预防的结构，了解这些限制的分子基础是至关重要的。在这个项目中，学生将：使用分子和细胞病毒学、基于FRET的分析和超分辨显微镜来研究环境/受体相互作用的聚集性和动力学如何在干扰素/IFITM耐药(年1-2年)中起作用。使用具有良好特征的队列中的患者样本，纵向克隆和表征患者的环境病毒，并确定中和抗体逃逸如何导致环境病毒中干扰素耐药性的丧失(2-3年)。

A key attribute for the transmission of HIV-1 between individuals is the virus's intrinsic resistance to the antiviral activities of type-1 interferons (IFN-I). Transmitted viruses have a higher resistance to IFN-I than those isolated from the recipient partner 6 months later. The effects of IFN-I on HIV-1 replication are mediated by interferon-induced genes (ISGs), several of which directly inhibit stages of the virus lifecycle. The Interferon-Induced Transmembrane Proteins (IFITMs) are broadly-acting ISGs that target the cell entry process that is mediated by its envelope glycoprotein (Env). We have found that transmitted HIV-1 strains are IFITM resistant but sensitivity increases over time as Env adapts to escape host antibody responses. Insensitivity to IFITMs contributes substantially to the IFN-I resistance of the transmitted virus. Preliminary data suggests that IFITM/IFN resistance of Env correlates with the structural rearrangements it must undergo when it binds to its receptor CD4. The more stable the Env, the more IFITM resistant. Thus the transmitted Env is structurally constrained by the need to be IFN-resistant. Since this is the structure that an effective vaccine needs to protect against, understanding the molecular basis of these constraints is essential. In this project the student will:. use molecular and cellular virology, FRET-based assays and super-resolution microscopy to study how the clustering and dynamics of Env/receptor interactions contribute to IFN/IFITM resistance (Yrs 1-2).. using patient samples from well characterized cohorts, clone and characterize Envs from patients longitudinally and determine how neutralizing antibody escape leads to loss of IFN resistance in Env (Yrs 2-3).