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: 10666594
• 负责人: Jeremy A O'Sullivan
• 金额: $ 48.84万
• 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/10666594
• 关键词: Active Sites; Address; Adherence; Area; Autopsy; Binding; Biological Assay; Blood; CD4 Positive T Lymphocytes; Cell Separation; Cells; Cessation of life; Chronic Disease; Collaborations; Colon; 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; Longevity; Lymphocyte; Macaca; Macrophage; Modeling; Mucous Membrane; Myelogenous; Myeloid Cells; Nature; Neuroimmune system; PET/CT scan; Pathogenesis; Patients; Peripheral; Persons; Phenotype; Play; Predisposition; Research Personnel; Resources; Role; SIV; Sampling; Signal Transduction; Site; Skin; Stimulus; Study models; T-Lymphocyte; Techniques; Technology; Testing; Time; Tissues; Toxic effect; Viral; Virus; Virus Replication; antiretroviral therapy; cell type; cost; design; forgetting; granulocyte; humanized mouse; in vivo; in vivo Model; innovation; insight; lymph nodes; 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.

项目摘要/摘要 对于许多艾滋病毒感染者，终身抗逆转录病毒疗法（CART）已转化HIV 从死亡判决到可控制的慢性疾病的流行病。但是，艾滋病毒水库仍然存在 在绝大多数患者的手推车中断时，经过治疗的个体和病毒反弹发生。鉴于 与终身购物疗法有关的挑战，例如依从性，病毒逃生，毒性和成本，发现 消除病毒和/或在没有卡车的情况下诱导持续的病毒控制的新方法是非常高的 艾滋病毒领域的优先级。组织是艾滋病毒潜伏期的主要部位，并在 购物车中断。我们的初步数据表明，SIV感染了肥大细胞（MC），一种粒细胞 源自髓样祖细胞可能具有重要的，尽管在艾滋病毒持续存在中具有重要的作用 组织。 MC有助于免疫和神经免疫系统，几乎完全居住在 结缔组织和皮肤。因此，到目前为止，MC的HIV感染及其在HIV中的潜在作用 在分离这些细胞和识别的罕见焦点时，储层受到了后勤困难的阻碍 组织中的HIV/SIV感染，尤其是在治疗过程中。我们团队的技术进步导致了 猕猴中抗逆转录病毒治疗中断后，在反弹时鉴定了SIV感染的MC。 反过来，这导致了体内研究和一组研究人员的初步数据 艾滋病毒和MC的专业知识。我们的初步数据强烈支持组织MC在HIV发病机理中的作用 和持久性。这些组织居民细胞的寿命比淋巴细胞更长，并且在 至少它可以与CD4+ T细胞相媲美。因此，我们建议使用各种独特的工具， 探索艾滋病毒感染的动态的资源，并解决了艾滋病毒感染MC的假设 在HIV组织储层中起重要作用。具体来说，我们将使用非人类隐私的时间 研究（AIM 1）将通过活性SIV鉴定的区域通过PET-CT指导采样收集 表达。我们将表征在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。我们将使用体内和体外感染（AIM 2）的人类肠道和皮肤衍生 MC了解艾滋病毒感染和持久性的动态以及不同刺激对艾滋病毒的影响 在存在和不存在购物车的情况下复制。最后，我们将使用MC的人源化鼠标模型（AIM 3） 调查与AIM 2 In Vivo或Ex Vivo相似的问题。总而言之，我们将 利用不同和互补模型和技术的工具箱来解决组织MC在 为艾滋病毒的持久性做出贡献，并确定如何操纵和针对这个“被遗忘”的水库 促进新型，更全面的HIV治疗策略的发展。