Exploration into the Forgotten HIV Reservoir with Models of HIV/SIV Persistence in Mucosal Tissues

利用粘膜组织中 HIV/SIV 持续存在的模型探索被遗忘的 HIV 病毒库

• 批准号: 10460078
• 负责人: Elena Martinelli
• 金额: $ 48.4万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460078
• 关键词: Active Sites; Address; Adherence; Area; Autopsy; Biological Assay; Blood; CD4 Positive T Lymphocytes; Cells; Cessation of life; Chronic Disease; Collaborations; Connective Tissue; Data; Development; Epidemic; Frequencies; Generations; Genetic Transcription; Goals; Greater sac of peritoneum; Gut Mucosa; HIV; HIV Infections; Human; Immune; Immune system; In Vitro; Individual; Infection; Interruption; Intervention; Logistics; Longevity; Lymphocyte; Macaca; Modeling; Mucous Membrane; Myelogenous; Myeloid Cells; Nature; Neuroimmune system; Pathogenesis; Patients; Peripheral; Persons; Phenotype; Play; Positron-Emission Tomography; Predisposition; Research Personnel; Resources; Role; SIV; Sampling; Signal Transduction; Site; Skin; Stimulus; Study models; T-Lymphocyte; Techniques; Testing; Time; Tissues; Toxic effect; Viral; Virus; Virus Replication; antiretroviral therapy; base; cell type; cost; design; granulocyte; humanized mouse; in vivo; in vivo Model; innovation; insight; lymph nodes; macrophage; mast cell; mouse model; mucosal site; nonhuman primate; nonhuman tissue; novel; progenitor; response; tool; viral rebound

PROJECT SUMMARY/ABSTRACT For many HIV infected people, lifelong combination antiretroviral therapy (cART) has converted the HIV epidemic from death sentence into a manageable chronic disease. However, the HIV reservoir persists in all treated individuals and viral rebound occurs upon cART interruption in the vast majority of patients. Given the challenges related to lifelong cART treatment such as adherence, viral escape, toxicity, and costs, finding novel ways to eradicate the virus and/or induce sustained virologic control in absence of cART is a very high priority in the HIV field. Tissues are major sites for HIV latency and notable contributors to viral rebound after cART interruption. Our preliminary data demonstrate that SIV infected mast cells (MC), a type of granulocyte derived from myeloid progenitors may have an important, albeit understudied role in the persistence of HIV in tissues. MC contribute to both the immune and neuroimmune systems and reside almost exclusively in connective tissues and skin. Hence, until now the study of HIV infection of MC and their potential role in HIV reservoir has been thwarted by logistical difficulties in both isolating these cells and identifying rare foci of HIV/SIV infection in tissues especially during therapy. The technological advancements of our team led to the identification of SIV infected MC at the time of rebound after antiretroviral treatment interruption in macaques. This, in turn, led to ex vivo studies and the generation of preliminary data by a team of investigators with expertise in both HIV and MC. Our preliminary data strongly support a role of tissue MC in HIV pathogenesis and persistence. These tissue resident cells live much longer than lymphocytes and susceptible to infection at least in a way that it is comparable to CD4+ T cells. Hence, we propose to use a variety of unique tools and resources to explore the dynamics of HIV infection ex vivo and address the hypothesis that HIV infected MC play an important role in the HIV tissue reservoir. Specifically, we will use tissues from non-human primate studies (Aim 1) that will be collected via PET-CT-guided sampling from areas identified with active SIV expression. We will characterize the frequency of infected CD4+ T cells and MCs in these areas during different types of interventions. We will use ex vivo and in vitro infection (Aim 2) of human gut and skin derived MC to understand the dynamics of HIV infection and persistence and the impact of different stimuli on HIV replication in presence and absence of cART. Finally, we will use a humanized mouse model of MC (Aim 3) to investigate questions similar to those addressed by Aim 2 either in vivo or ex vivo. In summary, we will leverage a toolbox of different and complementary models and techniques to address the role of tissue MC in contributing to HIV persistence and to determine how to manipulate and target this “forgotten” reservoir to facilitate the development of novel, more comprehensive HIV cure strategies.

项目概要/摘要 对于许多 HIV 感染者来说，终身联合抗逆转录病毒治疗 (cART) 已将 HIV 病毒转化为艾滋病病毒感染者。 流行病从死刑变成了可控制的慢性病。然而，艾滋病毒储存库仍然存在于所有 在接受治疗的个体中，绝大多数患者在 cART 中断后会发生病毒反弹。鉴于 与终身 cART 治疗相关的挑战，如依从性、病毒逃逸、毒性和成本，发现 在没有 cART 的情况下根除病毒和/或诱导持续病毒学控制的新方法是非常高的 优先考虑艾滋病毒领域。组织是艾滋病毒潜伏的主要场所，也是感染后病毒反弹的重要因素。 cART 中断。我们的初步数据表明，SIV 感染了肥大细胞 (MC)，这是一种粒细胞 源自骨髓祖细胞的细胞可能在 HIV 持续存在的过程中具有重要的作用，尽管这一作用尚未得到充分研究。 组织。 MC 对免疫和神经免疫系统都有贡献，并且几乎完全存在于 结缔组织和皮肤。因此，迄今为止，MC 的 HIV 感染及其在 HIV 中的潜在作用的研究 分离这些细胞和识别罕见病灶的后勤困难阻碍了储存库的发展 组织中的 HIV/SIV 感染，尤其是在治疗期间。我们团队的技术进步导致 猕猴抗逆转录病毒治疗中断后反弹时 SIV 感染 MC 的鉴定。 这反过来又导致了一组研究人员进行了离体研究并生成了初步数据 HIV 和 MC 方面的专业知识。我们的初步数据有力地支持了组织 MC 在 HIV 发病机制中的作用 和坚持。这些组织驻留细胞比淋巴细胞寿命长得多，并且容易受到感染 至少在某种程度上它与 CD4+ T 细胞相当。因此，我们建议使用各种独特的工具和 探索 HIV 离体感染动态并解决 HIV 感染 MC 的假设的资源 在 HIV 组织储存库中发挥重要作用。具体来说，我们将使用非人类灵长类动物的组织 研究（目标 1）将通过 PET-CT 引导的采样从已识别出活动性 SIV 的区域收集 表达。我们将描述这些区域中受感染的 CD4+ T 细胞和 MC 的频率 不同类型的干预措施。我们将利用人类肠道和皮肤衍生的离体和体外感染（目标2） MC了解HIV感染和持续性的动态以及不同刺激对HIV的影响 在存在和不存在 cART 的情况下进行复制。最后，我们将使用 MC 的人源化小鼠模型（目标 3） 在体内或离体研究与目标 2 所解决的问题类似的问题。总而言之，我们将 利用不同且互补的模型和技术的工具箱来解决组织 MC 在 有助于艾滋病毒的持续存在，并确定如何操纵和瞄准这一“被遗忘”的病毒库 促进新型、更全面的艾滋病毒治疗策略的制定。