HIV immune evasion and escape through T cell virological synapses

HIV-1是一种慢性感染，免疫系统不能自发清除。该病毒已 逃避免疫反应的显著能力，并产生高序列多样性， 净化选择的力量我们和其他人已经发现，病毒传播发生在体外和体内。 体内通过细胞-细胞接触，称为病毒学突触（VS），它掩盖了感染的免疫检测 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 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， 细胞表面我们认为，这些构象可以使感染的细胞相对于无细胞的“低抗原性”。 并进一步表明变构传感机制允许Env检测它是否与细胞相关， 或病毒体相关的。这些研究解决了一个关键问题，即如何在不同的环境中识别环境。 受感染细胞的表面以及细胞间的传播如何影响病毒逃逸。在VS形成环境期间 在作为病毒膜之前，作为感染和未感染细胞之间的细胞粘附受体发挥作用 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--以增强细胞间的传播。T细胞VS对细胞培养中的病毒传播至关重要 并在人源化小鼠的淋巴组织中体内发挥功能。VS传播促进有效免疫 逃避大多数广泛中和抗体（bNabs）在中和细胞间感染方面的效力低于 同样的病毒以无细胞形式存在。当针对传播的创始者克隆进行测试时，bNabs不完全抑制 在最大浓度下的细胞间感染，即显示降低的功效。我们建议定义细胞 降低的效力和针对VS的中和抗体的功效的潜在机制。 还测试了一个模型，说明艾滋病毒通过VS的多拷贝传播如何有助于维持多样化的 一群突变序列，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传播是一种关键免疫逃避和逃逸策略， 病毒持久性

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.