HIV immune evasion and escape through T cell virological synapses

HIV通过T细胞病毒学突触逃避免疫

• 批准号: 10225070
• 负责人: BENJAMIN K CHEN
• 金额: $ 53.85万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225070
• 关键词: Achievement; Address; Affect; Antibodies; Antibody Therapy; Bar Codes; Binding; Cell Adhesion; Cell Culture Techniques; Cell physiology; Cell surface; Cell-Cell Adhesion; Cells; Cellular biology; Chimeric Proteins; Color; Data; Defective Viruses; Detection; Dominant-Negative Mutation; Endocytosis; Epitopes; Gene Pool; Generations; HIV; HIV-1; Immune; Immune Evasion; Immune response; Immune system; In Vitro; Infection; Integration Host Factors; Knowledge; Lymphoid Tissue; Masks; Measures; Mediating; Membrane Fusion; Modeling; Molecular Conformation; Mutate; Preventive vaccine; Process; Recycling; Resistance; Role; Surface; T-Lymphocyte; TFAP2A gene; Tail; Testing; Therapeutic antibodies; Viral; Viral Proteins; Virion; Virus; Work; adhesion receptor; chronic infection; humanized mouse; in vivo; knock-down; mouse model; mutant; neutralizing antibody; novel therapeutics; novel vaccines; pressure; ratiometric; receptor; recruit; synaptogenesis; transmission process; vaccine development; virological synapse

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.

HIV-1 会造成免疫系统无法自发清除的慢性感染。该病毒有 逃避免疫反应并产生高序列多样性的非凡能力 净化选择的力量。我们和其他人发现病毒传播发生在体外和体内 体内通过细胞与细胞的接触，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，从而实现逃逸。我们的数据表明，HIV Env 病毒蛋白参与 VS 形成和病毒进入，在病毒上与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受感染的细胞相对于无细胞而言“低抗原性” 病毒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。这些研究解决了 Env 如何以不同方式识别的关键问题 受感染细胞的表面以及细胞间传播如何影响病毒逃逸。 VS 形成环境期间 在充当病毒膜之前，充当受感染细胞和未感染细胞之间的细胞粘附受体 融合蛋白。通过 VS HIV 利用细胞生物学——极化受体招募和病毒内吞作用 进入目标细胞——增强细胞间的传输。 T 细胞 VS 对于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发挥体内作用。 VS传输促进强效免疫 逃避。大多数广泛中和抗体（bNab）在中和细胞间感染方面的效力不如 无细胞形式的相同病毒。当针对传播的创始人克隆进行测试时，bNab 不完全抑制 在最大浓度下细胞间感染，即显示功效降低。我们建议定义蜂窝 VS 中和抗体效力和功效降低的机制。我们将 还测试了一个模型，了解 HIV 通过 VS 进行多拷贝传播如何有助于维持多样性 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 传播是一种关键的免疫逃避和逃逸策略，可驱动 病毒的持续存在。