Exploring the features of HIV exceptional elite controllers in humanized mice

探索人源化小鼠中艾滋病毒杰出精英控制者的特征

• 批准号: 10472752
• 负责人: Ramesh Akkina
• 金额: $ 19.34万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472752
• 关键词: Animal Model; Antibodies; Area; Autologous; Biological Assay; CD34 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Clinical; Colorado; Complex; Comprehension; DNA; Detection; Disease remission; Dose; Enterochromaffin Cells; Evaluation; Exhibits; Genetic Transcription; Goals; HIV; HIV Infections; HIV drug resistance; Hematopoietic stem cells; Human; Immune; Immune response; Immunologics; Immunology procedure; In Vitro; Individual; Infection; Inflammation; Investigation; Mediating; Modeling; Mus; Peripheral Blood Mononuclear Cell; Population; Proviruses; Recommendation; Residual state; Resistance; Resources; Role; Site; T cell response; T-Lymphocyte; Testing; Time; Umbilical Cord Blood; Universities; Viral; Viral Physiology; Viral reservoir; Virus; Virus Latency; Withdrawal; Work; base; cohort; experience; humanized mouse; in vivo; insight; novel; reconstitution; superinfection; viral detection

Project Summary/Abstract: Newer insights into long-term natural control of HIV infection in the absence of ART will inform efforts to induce a functional cure or “remission.” Recent work has identified a subset of HIV elite controllers (EC) who are considered “exceptional” (EEC) with decades of virologic control without immunologic decline. Multiple mechanisms likely contribute to control in EECs, including a potent and sustained CD8+ T cell response. However, it is unclear whether EECs can maintain this status indefinitely, whether they have any ongoing viral activity and benefit from initiation of ART (or are harmed by withdrawal of ART), or whether they spontaneously cleared viral reservoirs. Whether such individuals may represent a true model of durable HIV control or, in some cases, a functional cure are important questions needing further investigation. Leveraging the largest elite controller cohort in the USA, the UCSF SCOPE cohort, our recent work focused on the question: is there a subset of ECs that might serve as a model for long-term ART-free HIV remission? Using the new intact proviral DNA assay (IPDA) to detect intact proviruses as well as sensitive antibody and T-cell immune-assays, we identified a small subset of 21 exceptional ECs with ultra-low reservoir size. Recent analyses using a combination of IPDA and FLIP-seq suggested that some ECs have ultralow levels of intact proviruses existing in a deeply latent state making their detection difficult. Therefore, novel virological assays to detect ultralow levels of latent HIV and immunological analyses to evaluate the role of CD8+ T cell control need to be employed to further our understanding of EECs. Towards this goal, we propose to employ our new ultrasensitive in vivo humanized mouse viral outgrowth assay (hmVOA) model for latent viral detection. This model also provides a unique in vivo setting to examine the role of immune control since CD4+ T cells from the EEC can be tested for viral outgrowth in the presence or absence of autologous CD8+ T cells believed to mediate control which is otherwise not possible to evaluate in a human setting. While full comprehension of EECs is a complex undertaking, here we propose to start with simpler initial goals to: 1. Determine whether intact HIV can be recovered (via viral outgrowth) from exceptional elite controllers not currently on ART and elite controllers on long-term ART using the humanized mouse viral outgrowth (hmVOA) assay 2. Ascertain if the predominant viral control in EEC is indeed mediated by CD8+ T cells and assess if this control can also provide resistance to a potential new HIV exposure (superinfection) in vivo. Results from here will help in furthering our understanding of the latent virus and the role of strong cell-mediated virus control in EECs.

项目概要/摘要： 在没有抗逆转录病毒疗法的情况下，对艾滋病毒感染的长期自然控制的新见解将为诱导艾滋病毒感染的努力提供信息。 功能性治愈或“缓解”最近的工作已经确定了一个艾滋病毒精英控制者（EC）的子集，他们是 被认为是“例外”（EEC），具有数十年的病毒学控制而没有免疫学下降。多 这些机制可能有助于控制内皮细胞，包括有效和持续的CD 8 + T细胞应答。 然而，目前还不清楚EECs是否可以无限期地保持这种状态，它们是否有任何持续的病毒感染， 活动和受益于开始ART（或因ART停药而受到损害），或是否自发 清除了病毒库这些人是否代表了持久控制艾滋病毒的真正模式，或者在某些情况下， 在这些病例中，功能性治疗是需要进一步研究的重要问题。利用最大的精英 控制器队列在美国，加州大学旧金山分校范围队列，我们最近的工作集中在这个问题上：是否有一个 可以作为长期无ART HIV缓解模型的EC子集？使用新的完整前病毒 DNA检测（IPDA）检测完整的前病毒以及敏感的抗体和T细胞免疫测定，我们 确定了21个具有超低储层大小的特殊EC的一小部分。最近的分析使用的组合 IPDA和FLIP-seq的结果表明，一些EC在深层组织中存在超低水平的完整前病毒， 使其难以检测的潜在状态。因此，新的病毒学检测，以检测超低水平的潜伏性 HIV和免疫学分析来评估CD 8 + T细胞控制的作用，需要进一步我们的研究。 了解EECs。为了实现这一目标，我们建议采用我们的新的超灵敏的体内人源化 用于潜伏病毒检测的小鼠病毒生长测定（hmVOA）模型。该模型还提供了一个独特的体内 设置检查免疫控制的作用，因为可以测试来自EEC的CD 4 + T细胞的病毒生长 在存在或不存在被认为介导对照的自体CD 8 + T细胞的情况下， 可以在人类环境中评估。虽然完全理解EEC是一项复杂的任务，但在这里， 建议从更简单的初始目标开始： 1.确定完整的HIV是否可以从特殊的精英控制者身上恢复（通过病毒生长）， 目前使用ART和精英控制器使用人源化小鼠病毒产物（hmVOA）进行长期ART 测定 2.确定EEC中的主要病毒控制是否确实由CD 8 + T细胞介导，并评估该控制是否 还可以提供对体内潜在的新的HIV暴露（重复感染）的抗性。 从这里的结果将有助于进一步了解潜伏病毒和强大的细胞介导的作用， 病毒控制在EECs中。