Project 3 - Dynamics of latent HIV-1 reservoirs: High resolution antigenic mapping and strategies to block rebound

项目 3 - 潜在 HIV-1 储存库的动态：高分辨率抗原图谱和阻止反弹的策略

• 批准号: 10506669
• 负责人: Priyamvada Acharya
• 金额: $ 87.01万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-14 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10506669
• 关键词: AIDS/HIV problem; Affect; Antibodies; Antigens; Autologous; B-Lymphocytes; Binding; Biological Assay; Complex; Cryo-electron tomography; Cryoelectron Microscopy; Data; Development; Disease remission; Electron Microscopy; Epitopes; Evolution; Excision; Fab Immunoglobulins; Goals; Growth; HIV; HIV-1; Immune system; Immunoglobulin G; In Vitro; Individual; Infection; Interruption; Knowledge; Maps; Measures; Mediating; Membrane; Modality; Molecular; Monoclonal Antibodies; Negative Staining; Persons; Polysaccharides; Population; Prevention; Process; Property; Proviruses; Research; Resistance; Resolution; Rest; Sampling; Specificity; Structure; Testing; Therapeutic; Vaccines; Variant; Viral; Viral reservoir; Viremia; Virion; Virus; Virus Latency; X-Ray Crystallography; antiretroviral therapy; base; env Gene Products; expectation; experimental study; in vivo; individualized medicine; latent HIV reservoir; memory CD4 T lymphocyte; neutralizing antibody; prevent; resistance mechanism; response; structural biology; targeted treatment; viral rebound; virus envelope

Abstract – Project 3 Approximately 40 million people worldwide are living with HIV/AIDS; however, a protective vaccine or functional cure remain elusive despite four decades of intense research. HIV-1 evades the immune system through its rapid structural evolution during infection and replication. The latent reservoir in resting memory (RM) CD4+ T cells is the major barrier to curing HIV-1 infection. Established early during infection, the latent reservoir is extremely stable, and persists despite long-term antiretroviral therapy (ART). When latently infected RM CD4+ T cells are activated in vivo, they can begin to produce HIV virions again, resulting in exponential viral growth and rebound viremia if ART has been interrupted. Eradicating this latent viral reservoir to achieve cure from HIV- 1 has been a long-sought goal that has been difficult to achieve. An alternate approach is to delay or reduce rebound from latent reservoirs allowing sustained ART-free remission. A recent study from the Siliciano lab has shown that autologous neutralizing antibodies (anAbs) directed at the HIV-1 Envelope (Env) protein suppress outgrowth of a substantial but variable fraction of reservoir viruses in vitro. This effect was attributed to neutralizing activity of anAbs, and provides proof-of-principle for the feasibility of Ab-mediated prevention of viral rebound from latent reservoirs. Moreover, by demonstrating that anAbs block the outgrowth of a substantial population of the replication-competent viruses in the latent reservoir, these results effectively reduce the magnitude of the problem of controlling rebound to the subset of reservoir viruses that are resistant to anAbs. In this project, we will visualize the binding of anAbs to the Envs of sensitive viruses. Further, we will determine atomic level structures of Envs from the viruses resistant to anAbs to understand the molecular basis for their resistance, and to define their vulnerabilities. Thus, the overall goal of this study is an atomic level understanding of antibody-mediated control of rebound from latent HIV-1 reservoirs. To achieve this goal, we will aim to 1) define the epitope specificities of anAbs that suppress outgrowth of a substantial population of the replication- competent proviruses in the latent HIV-1 reservoir; 2) define mechanisms of resistance of rebound viruses to neutralization by anAbs; and 3) define the evolution of the anAb response in HIV-1 infected individuals to understand its effect on the seeding of the latent reservoir and its impact on rebound viremia. At the culmination of this study, we expect to have defined, structurally and antigenically, the common features of the anAb resistant Envs that the can be targeted to prevent rebound.

摘要 – 项目 3 全世界大约有 4000 万人感染了艾滋病毒/艾滋病，但是，保护性疫苗或功能性药物； 尽管经过四十年的深入研究，HIV-1 通过其免疫系统逃避，但治愈方法仍然难以实现。 感染和复制过程中的快速结构进化。静息记忆 (RM) CD4+ T 中的潜在储存库。 细胞是治愈 HIV-1 感染的主要障碍，潜伏病毒库在感染早期就已建立。 非常稳定，并且即使长期抗逆转录病毒治疗（ART），当潜伏感染 RM CD4+ 时仍持续存在。 T细胞在体内被激活，它们可以再次开始产生HIV病毒体，导致病毒呈指数级增长 如果ART被中断，病毒血症就会反弹，消除这种潜在的病毒库以实现艾滋病毒的治愈。 1 一直是一个长期追求的目标，但一直难以实现。另一种方法是推迟或减少。 Siliciano 实验室最近的一项研究表明，潜伏病毒库的反弹可以实现持续的无 ART 缓解。 研究表明，针对 HIV-1 包膜 (Env) 蛋白的自体中和抗体 (anAbs) 会抑制 这种效应归因于体外大量但可变部分的储存病毒的生长。 抗体的中和活性，并为抗体介导的病毒预防的可行性提供原理证明 此外，通过证明抗体可以阻止大量抗体的生长。 潜伏病毒库中具有复制能力的病毒种群，这些结果有效地减少了 控制对抗体具有抗性的储存病毒子集的反弹问题的严重程度。 在这个项目中，我们将可视化抗体与敏感病毒的包膜的结合。此外，我们将确定。 抗抗体的病毒的包络体的原子水平结构，以了解其抗性的分子基础 因此，本研究的总体目标是原子级别的理解。 抗体介导的控制潜伏 HIV-1 病毒库反弹的方法 为了实现这一目标，我们的目标是 1) 定义抑制大量复制群体生长的抗体的表位特异性 潜伏 HIV-1 病毒库中的活性原病毒；2) 确定反弹病毒的抵抗机制 anAb 的中和作用；以及 3) 定义 HIV-1 感染个体中 anAb 反应的演变 了解其对潜伏病毒库播种的影响及其对病毒血症顶峰反弹的影响。 在这项研究中，我们希望从结构和抗原上确定 anAb 抗性的共同特征 恩维斯认为，可以有针对性地防止反弹。