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: 10484093
• 负责人: BENJAMIN K CHEN
• 金额: $ 61.67万
• 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 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10484093
• 关键词: Antibodies; Antibody Response; Bar Codes; Binding; Biochemical; Biological Assay; Biotin; Cell Adhesion; Cell Culture Techniques; Cell physiology; Cell surface; Cells; Cellular biology; Chimeric Proteins; Combined Modality Therapy; Data; Detection; Endocytosis; Endosomes; Epitopes; Evolution; Face; Genes; Glycoproteins; HIV; HIV-1; Heterogeneity; Image; Immune; Immune Evasion; Immune response; Immune system; In Vitro; Infection; Knowledge; Label; Lymphoid Tissue; Masks; Measures; Mediating; Membrane Fusion; Modeling; Molecular Conformation; Mutate; Pathway interactions; Pattern; Peptides; Play; Process; Recycling; Role; Shapes; Signal Transduction; Surface; T-Lymphocyte; Testing; Therapeutic antibodies; Viral; Viral Proteins; Virion; Virus; Virus Diseases; Work; adhesion receptor; chronic infection; genetic manipulation; glycosylation; gp160; humanized mouse; improved; in vivo; inhibitor; mouse model; mutant; neutralizing antibody; novel vaccines; pressure; ratiometric; receptor; recruit; response; single-cell RNA sequencing; synaptogenesis; synergism; trafficking; transmission process; vaccine-induced antibodies; virological synapse

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.

项目摘要 HIV-1建立了一种慢性感染，即免疫系统无法自发清除。该病毒有一个 逃避免疫反应并产生高序列多样性的显着能力 缺陷基因。我们和其他人发现，病毒传播是在体外和体内进行的 通过称为病毒学突触（VS）的细胞细胞触点，可以帮助掩盖免疫检测感染 细胞，并促进能够逃脱的病毒式准物质多样性。我们的数据表明，中央 在细胞到细胞传播过程中，对参与VS形成和病毒的病毒蛋白进行了调节 并假定在细胞表面与病毒颗粒上具有不同的构象。我们检查了多么低 ENV在细胞表面的丰度，快速营业率和处理的异质性有助于减少 与丰富的无细胞病毒或脱落糖蛋白相比，感染细胞的抗原性。研究 在这里提出的测试模型，通过该模型，ENV运输的顺序 - 到细胞表面，再回收 内体，然后是病毒粒子 - 支持该途径的不同抗原状态。在先验中 研究期我们了解到，在与形成期间，env充当细胞粘附受体 感染和未感染的细胞在其作用为病毒膜融合蛋白之前。 HIV利用细胞生物学 包括极化受体募集和病毒内吞作用，以增强细胞到细胞 传播。 T细胞VS对于在细胞培养中的病毒传播和体内功能至关重要 人源化的小鼠。最广泛的中和抗体（BNAB）在中和细胞中的有效性较小 感染比无细胞形式的同一病毒。当针对传输的创始人克隆测试时，bnabs 通常无法以最大浓度抑制100％的细胞间感染，即表现出降低的功效。 在这些研究的继续，我们将定义降低效力的基础机制 和对V的中和抗体的功效。我们还将测试一个模型，以了解多拷贝 艾滋病毒通过vs传播有助于维持各种突变序列或 准特性，可以促进免疫逃生。我们假设细胞到细胞HIV-1传输是关键 免疫逃避和逃避策略，驱动病毒持久性。