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: 10643926
• 负责人: Priyamvada Acharya
• 金额: $ 118.89万
• 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/10643926
• 关键词: Affect; Antibodies; Antibody Response; Antibody Specificity; Antigens; Autologous; B-Lymphocytes; Binding; Biological Assay; Blocking Antibodies; Complex; Cryo-electron tomography; Cryoelectron Microscopy; Data; Development; Disease remission; Electron Microscopy; Epitopes; Evolution; Excision; Fab Immunoglobulins; Goals; Growth; HIV; HIV-1; HIV/AIDS; Immune Evasion; Immune system; Immunoglobulin G; In Vitro; Individual; Infection; Interruption; Knowledge; Maps; Measures; Mediating; Membrane; Modality; Molecular; Monoclonal Antibodies; Negative Staining; Persons; Polysaccharides; Population; Predisposition; Prevention; Process; Property; Proteins; Proviruses; Research; Resistance; Resolution; Rest; Sampling; Sorting; Specificity; Structure; T-Cell Activation; Testing; Therapeutic; Vaccines; Variant; Viral; Viral reservoir; Viremia; Virion; Virus; Virus Latency; Visualization; X-Ray Crystallography; antiretroviral therapy; expectation; experimental study; in vivo; individualized medicine; latent HIV reservoir; memory CD4 T lymphocyte; neutralizing antibody; prevent; resistance mechanism; structural biology; targeted treatment; viral rebound

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 全世界约有4000万人感染艾滋病毒/艾滋病;然而，保护性疫苗或功能性疫苗 尽管进行了40年的深入研究，但治愈方法仍然难以捉摸。HIV-1通过其免疫系统逃避免疫系统 在感染和复制过程中的快速结构进化。静息记忆（RM）中的潜在储存库CD 4 + T 细胞是治愈HIV-1感染的主要障碍。在感染早期建立，潜伏的水库是 非常稳定，尽管长期抗逆转录病毒治疗（ART）仍然存在。当潜伏感染RM CD 4+时 T细胞在体内被激活，它们可以开始再次产生HIV病毒体，导致病毒的指数增长 如果ART中断，病毒血症会反弹。根除这种潜伏的病毒库以治愈艾滋病毒- 1一直是一个长期追求的目标，一直难以实现。另一种方法是延迟或减少 从潜在的水库反弹，允许持续的无ART缓解。Siliciano实验室最近的一项研究表明， 显示针对HIV-1包膜（Env）蛋白的自体中和抗体（anAb）抑制了 在体外，大量但可变部分的储库病毒的生长。这种影响归因于 中和活性，并为Ab介导的预防病毒感染的可行性提供了原理证明。 从潜在储层中反弹。此外，通过证明抗体阻断了大量的 在潜伏库中的复制能力病毒的群体，这些结果有效地减少了 控制反弹至对anAb具有抗性的储库病毒子集的问题的严重性。在 在这个项目中，我们将可视化anAb与敏感病毒Envs的结合。此外，我们将确定 来自抗anAb病毒的Env的原子水平结构，以了解其分子基础。 抵抗力，并确定其脆弱性。因此，本研究的总体目标是在原子水平上理解 抗体介导的控制从潜伏的HIV-1储库反弹。为了实现这一目标，我们将致力于1） 定义抑制大量复制群体生长的抗体的表位特异性， 在潜伏的HIV-1储库中有能力的前病毒; 2）确定反弹病毒对 通过anAb中和;和3）定义HIV-1感染个体中anAb应答的演变， 了解它对潜伏病毒库的播种作用及其对反弹病毒血症的影响。在高潮时 通过这项研究，我们希望在结构和抗原性上确定抗AnAb耐药的共同特征， 认为可以有针对性的防止反弹。