HIV immune evasion and escape through T cell virological synapses

项目摘要 HIV-1是一种慢性感染，免疫系统不能自发清除。该病毒具有 逃避免疫应答的显著能力，并产生高序列多样性， 缺陷基因我们和其他人已经发现病毒传播在体外和体内都发生 通过细胞间的接触，称为病毒学突触（VS），这可以帮助掩盖感染的免疫检测。 细胞，并促进病毒准种多样性，使逃脱。我们的数据表明，艾滋病毒Env，中央 一种参与VS形成和病毒进入的病毒蛋白，在细胞间传播过程中受到调节 并在细胞表面呈现与病毒颗粒不同的构象。我们研究了 Env在细胞表面的丰度、快速周转和加工的异质性有助于减少 与大量的无细胞病毒或脱落糖蛋白相比，感染细胞的抗原性。研究 这里提出的测试模型，其中的序列Env运输-细胞表面，再循环 内体，然后到病毒颗粒--支持沿着这条途径的不同抗原状态。现有 研究期间，我们已经了解到，在VS形成过程中，Env作为细胞粘附受体， 感染和未感染的细胞，在其作为病毒膜融合蛋白的作用之前。艾滋病毒利用细胞生物学 包括极化受体募集和病毒内吞进入靶细胞，以增强细胞间的相互作用。 传输T细胞VS对于细胞培养物中的病毒传播和体内淋巴组织中的功能是关键的。 人源化小鼠。大多数广泛中和抗体（bNAb）在中和细胞间 感染比相同的病毒在无细胞形式。当针对传播的创始人克隆进行测试时，bNAb 在最大浓度下经常不能抑制100%的细胞间感染，即表现出降低的功效。 在这些研究的继续中，我们将确定降低效力的细胞机制 中和抗体对VS的效力。我们还将测试一个模型， 通过VS传播HIV有助于维持突变序列的多样性群体，或 准种，促进免疫逃逸。我们假设细胞间的HIV-1传播是一个关键因素， 免疫逃避和逃逸策略驱动病毒的持久性。

Project Summary HIV-1 establishes a chronic infection that the immune system cannot spontaneously clear. The virus has a remarkable capacity to evade immune responses and generates a high sequence diversity that tolerates defective genes. We and others have found that viral dissemination takes place both in vitro and in vivo through cell-cell contacts, called virological synapses (VS), which can help mask immune detection of infected cells, and promote viral quasispecies diversity that enable escape. Our data indicate that HIV Env, the central viral protein involved in VS formation and viral entry, is regulated during the process of cell-to-cell transmission and assumes distinct conformations on the cell surface versus the virus particle. We examine how low abundance, rapid turnover and heterogeneity of processing of Env at the cell surface contributes to diminished antigenicity of infected cells as compared to abundant cell-free virus or shed glycoprotein. The studies proposed here test a model whereby the sequence of Env trafficking--to the cell surface, to the recycling endosome, and then to the virus particle--supports distinct antigenic states along this pathway. In the prior study periods we have learned that during VS formation Env works as a cell adhesion receptor between the infected and uninfected cell, prior to its role as viral membrane fusion protein. HIV exploits cell biology including the polarized receptor recruitment and viral endocytosis into the target cell, to enhance cell-to-cell transmission. The T cell VS is critical for viral spread in cell culture and functions in vivo in lymphoid tissues of humanized mice. Most broadly neutralizing antibodies (bNAbs) are less potent at neutralizing cell-to-cell infection than the same virus in a cell-free form. When tested against transmitted founder clones, bNAbs frequently fail to inhibit 100% of cell-to-cell infection at maximum concentration, i.e. display reduced efficacy. In the continuation of these studies, we will define the cellular mechanisms underlying the reduced potency and efficacy of neutralizing antibodies against the VS. We will also test a model for how the multicopy transmission of HIV through VS contributes to maintaining a diverse swarm of mutated sequences, or quasispecies, that promotes immune escape. We hypothesize that cell-to-cell HIV-1 transmission is a pivotal immune evasion and escape strategy that drives viral persistence.