HIV immune evasion and escape through T cell virological synapses

项目摘要 HIV-1建立了一种免疫系统无法自发清除的慢性感染。这种病毒有一种 卓越的逃避免疫反应的能力，并产生高度的序列多样性，耐受 有缺陷的基因。我们和其他人发现，病毒在体外和体内都有传播。 通过细胞间的接触，称为病毒学突触(VS)，它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，使之能够逃脱。我们的数据表明，艾滋病毒环境中心 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。 并在细胞表面相对于病毒颗粒呈现不同的构象。我们检查了有多低 Env在细胞表面的丰富、快速周转和异质性处理有助于减少 与大量无细胞病毒或脱落糖蛋白相比，感染细胞的抗原性。这些研究 这里提出了一个模型，在这个模型中，环境运输的序列--到细胞表面，再到回收 内体，然后到病毒颗粒--沿着这一途径支持不同的抗原状态。在前一次 研究期间，我们了解到在VS形成过程中，Env作为细胞黏附受体在VS形成过程中发挥作用 感染和未感染的细胞，之前其作为病毒膜融合蛋白的作用。HIV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 变速箱。T细胞VS对病毒在细胞培养中的传播和在体内淋巴组织中的功能至关重要 人性化的老鼠。大多数广谱中和抗体(BNAbs)对细胞间的中和能力较弱。 感染比同样的病毒在无细胞状态下。当与传输的方正克隆进行测试时，bNAbs 通常不能在最大浓度下100%抑制细胞间的感染，即显示效果降低。 在这些研究的继续过程中，我们将确定效力降低背后的细胞机制。 以及中和抗体对VS的疗效。我们还将测试一个模型，以了解多副本 通过VS传播HIV有助于维持不同的突变序列群，或 准种，促进免疫逃逸。我们假设HIV-1的细胞间传播是 免疫逃避和逃逸策略，推动病毒持续存在。

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.