Immunotherapy to enhance anti-HIV-1 responses against viral brain infection

免疫疗法增强抗 HIV-1 反应，对抗病毒性脑部感染

• 批准号: 9893898
• 负责人: James R Lokensgard
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893898
• 关键词: Acute; Adenovirus Vector; Adoptive Transfer; Advanced Malignant Neoplasm; Affect; Animal Model; Anti-Inflammatory Agents; Antiviral Agents; Apoptosis; Area; Astrocytes; Biological Assay; Brain; CD8-Positive T-Lymphocytes; CD8B1 gene; Capsid Proteins; Cell Survival; Cells; Cytotoxic T-Lymphocytes; Epitopes; FOXP3 gene; Funding; Grant; HIV; HIV-1; Immune; Immunization; Immunotherapeutic agent; Immunotherapy; In Vitro; Infection; Inflammatory Response; Investigational Therapies; Lead; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Microglia; Mus; Neuroglia; Organ; Pathway interactions; Patients; Peptides; Plasma; Predisposition; Property; Proteins; Regulatory T-Lymphocyte; Research; Role; T cell response; T memory cell; T-Lymphocyte; Therapeutic; Transgenic Mice; Up-Regulation; Viral; Viral Encephalitis; Viral Load result; Viral reservoir; Virus; Virus Diseases; Virus-like particle; anti-PD-1; antiretroviral therapy; antiviral immunity; cancer immunotherapeutics; cell type; cellular targeting; cytokine; diphtheria toxin receptor; exhaustion; experimental study; immune checkpoint; immune checkpoint blockade; in vivo; individual patient; individual response; inflammatory milieu; innovation; knockout animal; mouse model; novel; novel strategies; prevent; programmed cell death ligand 1; programmed cell death protein 1; recombinant adenovirus; response

PROJECT SUMMARY/ABSTRACT Immunotherapeutic approaches which target the programmed cell death protein (PD)-1 co-inhibitory immune checkpoint have revolutionized treatment of several types of advanced cancer. However, the susceptibility of particular cell types remains highly variable and difficult to predict. We have found that both microglial cells and astrocytes govern the activity of brain-infiltrating antiviral T-cells through upregulation of PD-L1 expression in an effort to limit damaging encephalitic responses. Likewise, we have found that CD4(+) regulatory T-cells (Tregs) limit viral encephalitis through restraining expansion and activity of CD8(+) cytotoxic T-lymphocytes. While these anti-inflammatory responses within the brain are undoubtedly beneficial to the host, preventing immune-mediated damage to this vital organ, establishment of a prolonged anti-inflammatory milieu may also lead to deficiencies in viral clearance. Patients undergoing successful cART are viremically suppressed in both plasma and CSF, but persisting HIV-1 reservoirs are believed to contribute to the inability to completely cure infection. HIV-specific CD8(+) T-cell responses are critical in suppressing acute viral infection within the brain, but ultimately fail in their ability to fully eradicate virus. It is currently unknown whether glia are viable cellular targets for immune checkpoint blockade or Treg modulation. Studies proposed here are intended to fill this critical void in our understanding of how the immunosuppressive, neuroprotective brain microenvironment complicates complete clearance of viral infection. Building on our previous studies, we have developed an innovative experimental murine model in which strong CD8(+) T-cell responses specific for immunodominant HIV-1 Gag epitopes are generated within the brains of mice via heterologous prime-boost immunization with recombinant adenovirus vectors expressing the p24 capsid protein (rAd5-p24), followed by a CNS boost using Pr55Gag/Env virus-like particles (HIVLPs). This novel approach allows us to investigate the effects of immunotherapy on viral clearance from the brain in a powerful, yet convenient and inexpensive small animal model. The proposed studies will first determine whether glial cells restrain T-cell-mediated clearance of viral infection through the PD-1: PD-L1 negative immune checkpoint. Experiments proposed in Aim #2 will go on to determine whether loss or blockade of the PD-1: PD-L1 axis will facilitate anti-HIV-1 T-cell-mediated viral clearance from the brain. Finally, in Specific Aim #3 we will determine whether modulation of Treg cell activity in combination with immune checkpoint blockade will further stimulate anti-HIV-1 T-cells to promote viral clearance. The potentially synergistic combination of immune checkpoint blockade and Treg modulation is currently an area of intense investigation for treatment of a variety of immunosuppressive cancers. One of the highest priorities in contemporary HIV-1 research is to identify strategies to effect a functional cure, in which viral load is fully suppressed for extended periods in the absence of antiretroviral therapy. These studies will determine whether immunotherapy can be used to reverse immune exhaustion against the viral brain reservoir.

项目摘要/摘要 靶向编程细胞死亡蛋白（PD）-1共抑制性免疫的免疫治疗方法 检查站已经彻底改变了对几种晚期癌症的治疗。但是， 特定的细胞类型仍然很可变且难以预测。我们发现两个小胶质细胞 星形胶质细胞通过上调PD-L1表达来控制脑浸润抗病毒T细胞的活性 为了限制损害脑反应。同样，我们发现CD4（+）调节T细胞 （Treg）通过限制CD8（+）细胞毒性T淋巴细胞的扩张和活性来限制病毒脑炎。 尽管大脑内的这些抗炎反应无疑对宿主有益，以防止 免疫介导的对这一重要器官的损害，建立长时间的抗炎环境也可能 导致病毒清除的缺陷。在两者中，经过成功的购物车的患者都被病毒抑制 血浆和CSF，但持续存在的HIV-1储层被认为有助于完全治愈 感染。 HIV特异性CD8（+）T细胞反应对于抑制大脑内的急性病毒感染至关重要， 但最终无法完全消除病毒的能力。目前尚不清楚神经胶质是否可行 免疫检查点封锁或Treg调制的目标。这里提出的研究旨在填补这一点 在理解免疫抑制，神经保护性脑微环境中的关键空隙 使病毒感染的完全清除率复杂化。在我们以前的研究的基础上，我们开发了 创新的实验鼠模型，其中强的CD8（+）T细胞反应特异 HIV-1堵嘴表位是在小鼠的大脑中通过异源质子促进免疫产生的 表达P24衣壳蛋白（RAD5-P24）的重组腺病毒载体，然后使用CNS增强 PR55GAG/ENV病毒样颗粒（HIVLP）。这种新颖的方法使我们能够研究 在一种强大但方便且廉价的小动物中，从大脑的病毒清除方面进行免疫疗法 模型。拟议的研究将首先确定神经胶质细胞是否限制了T细胞介导的病毒清除率 通过PD-1：PD-L1阴性免疫检查点的感染。 AIM＃2中提出的实验将继续 确定PD-1：PD-L1轴的损失或阻断是否会促进抗HIV-1 T细胞介导的病毒 大脑清除。最后，在特定的目标＃3中，我们将确定是否调制Treg细胞活动 结合免疫检查点封锁将进一步刺激抗HIV-1 T细胞以促进病毒 清除。免疫检查点封锁和Treg调制的潜在协同组合是 目前，对各种免疫抑制癌症进行了严格的研究。中的一个 当代HIV-1研究中的最高优先事项是确定实现功能治疗的策略，其中 在没有抗逆转录病毒疗法的情况下，病毒载量已完全抑制长时间。这些研究会 确定是否可以使用免疫疗法来逆转对病毒脑库的免疫衰竭。