HIV immune evasion and escape through T cell virological synapses

HIV-1建立了一种免疫系统无法自发清除的慢性感染。这种病毒已经 一种非凡的逃避免疫反应的能力，并产生高度的序列多样性，这与 净化选择的力量。我们和其他人发现病毒传播在体外和体内都有发生。 活体通过细胞间的接触，称为病毒学突触(VS)，它掩盖了对感染的免疫检测 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，在病毒上呈现不同的构象，而在病毒上 细胞表面。我们认为，这些构象可以使受感染的细胞成为相对无细胞的“低抗原性”细胞。 并进一步表明，变构感应机制允许Env检测它是否与细胞相关 或病毒粒子相关。这些研究解决了环境如何被不同地识别的关键问题 受感染细胞的表面，以及细胞间传播如何影响病毒逃逸。在VS队形环境中 作为感染细胞和未感染细胞之间的细胞黏附受体，在其作为病毒膜之前起作用 融合蛋白。通过VS HIV利用细胞生物学--极化受体募集和病毒内吞作用 进入目标细胞--以增强细胞间的传递。T细胞VS是病毒在细胞培养中传播的关键 并在人源化小鼠的淋巴组织中发挥体内作用。VS传播促进强大的免疫力 逃避。大多数广谱中和抗体(Bnab)在中和细胞间感染方面不如 同样的病毒以无细胞的形式存在。当与传播的方正克隆进行测试时，bNAb不完全抑制 最大浓度的细胞间感染，即表现出较低的疗效。我们建议定义细胞 抗VS的中和抗体效力和疗效降低的机制。我们会 还要测试一个模型，看看艾滋病毒通过VS的多拷贝传播如何有助于保持多样性 一大群突变的序列，或准种，可以让艾滋病毒轻松逃脱免疫压力。我们 假设细胞间HIV-1传播是一种关键的免疫逃避和逃避策略， 病毒持久力。

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 defies the forces of purifying selection. 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 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, assumes distinct conformations on viruses versus on the cell surface. We propose that these conformations can render infected cells as “hypoantigenic” relative to cell-free virus and further suggest that allosteric sensing mechanisms allow Env to detect whether it is cell-associated or virion-associated. The studies address the key problem of how Env is recognized differently on the surface of infected cells and how cell-cell transmission affects viral escape. 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. Through the VS HIV exploits cell biology -- 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. VS transmission facilitates potent immune evasion. 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 incompletely inhibit cell-to-cell infection at maximum concentration, i.e. display reduced efficacy. We propose to 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 can allow HIV to easily escape immune pressures. We hypothesize that cell-to-cell HIV-1 transmission is a pivotal immune evasion and escape strategy that drives viral persistence.