Immune based interventions for HIV eradication

基于免疫的干预措施消灭艾滋病毒

• 批准号: 9199852
• 负责人: Mirko Paiardini
• 金额: $ 86.11万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-06 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199852
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Animal Model; Animals; Anti-Retroviral Agents; Antibodies; Antiviral Agents; Antiviral Response; Automobile Driving; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Maintenance; Cells; Chronic; Clinical; Clinical Management; Clinical Trials; Combined Modality Therapy; Consensus; Data; Defensins; Development; Disease; Epithelial; Equilibrium; FDA approved; Genetic Transcription; Goals; HIV; HIV Infections; Homeostasis; Human; Immune; Immune System Diseases; Immune System and Related Disorders; Immune response; Individual; Infection; Inflammation; Interferon Type I; Interferon-alpha; Interferons; Interruption; Intervention; Intestines; Lead; Macaca mulatta; Mediating; Memory B-Lymphocyte; Modeling; Molecular; Natural Killer Cells; Organ; Plasma Cells; Primates; Proteins; Regimen; Regulatory T-Lymphocyte; Research; Residual Tumors; Residual state; SIV; Safety; Series; Testing; Therapeutic; Tight Junctions; Tissues; Viral reservoir; Virus; Virus Diseases; Virus Latency; Virus Replication; animal resource; base; cost; cytokine; exhaustion; experience; global health; human disease; immune checkpoint; immune function; immunoregulation; improved; in vivo; interleukin-21; novel; novel strategies; novel therapeutics; pre-clinical; premature; public health relevance; reconstitution; response; senescence; viral rebound

 DESCRIPTION (provided by applicant): Despite many major advances in AIDS research, including the development and optimization of potent anti- retroviral therapy (ART) that successfully suppresses virus replication in the majority of HIV-infected individuals, a treatment that can cure this deadly infection is still not available. Residual disease in ART-treated HIV-infected individuals consists mainly of (i) persistent immune abnormalities (including inflammation, limited CD4 T cell reconstitution, and premature immune senescence) which may ultimately lead to the so-called "HIV- associated end-organ diseases", and (ii) the presence of persistent reservoirs of latently infected cells that are not affected by ART and are responsible for the rapid rebound of virus replication if ART is stopped. In the absence of a scalable treatment able to cure HIV infection, ART is a lifelong treatment that poses significant challenges in terms of costs and clinical safety. For these reasons, eradicating or at least functionally curing HIV infection would have a remarkable impact on global health. Residual inflammation may promote HIV persistence under ART by several mechanisms, including driving the infection of susceptible cells that sustain the persistence of the reservoir, and the exhaustion of HIV-specific antiviral immune responses. Thus, a vicious cycle may be triggered in which residual inflammation, ineffective antiviral immune responses, and HIV persistence are intimately connected. As such, there is a strong consensus that a cure for HIV infection will not be achieved through ART intensification alone, and that novel approaches aimed at limiting residual inflammation and improving antiviral immune responses may be needed. The overarching goal of this project is to explore the therapeutic potential of a novel, combined Interleukin (IL)-21 and Interferon-a (IFNa) intervention in ART-treated SIV-infected rhesus macaques (RMs). We propose that the sequential administration of IL-21 and IFNa is safe and will have a strong synergistic effect on HIV persistence by decreasing immune dysfunction and inflammation (via IL-21), as well as enhancing antiviral functions mediated by a number of host restriction factors (via IFNa). These hypotheses will be tested in Aims 1 and 2. Moreover, we are proposing a series of mechanistic studies aimed at defining the molecular and cellular effects of sequential administration of IL-21 and IFNa [Aim 3]. If our hypothesis is correct, the proposed studies will provide in vivo evidence of reduced inflammation, improved immune function, and decreased virus reservoirs following sequential IL-21 and IFNa treatment in the most relevant preclinical animal model of HIV infection and using two molecules that, as a single agent, are being tested (IL-21) or approved by the FDA (IFNa) for treatment of several human diseases. If successful, the proposed immune based intervention would then be tested in human clinical trials to assess its potential as a functional cure for HIV infection.

 描述(申请人提供)：尽管艾滋病研究取得了许多重大进展，包括开发和优化了有效的抗逆转录病毒疗法(ART)，成功地抑制了大多数艾滋病毒感染者的病毒复制，但仍然没有治愈这种致命感染的治疗方法。经ART治疗的HIV感染者的残留疾病主要包括(I)持续性免疫异常(包括炎症、有限的CD4T细胞重建和过早的免疫衰老)，最终可能导致所谓的“HIV相关终末器官疾病”，以及(Ii)持续的潜伏感染细胞的存在，这些细胞不受ART的影响，并且在ART停止时导致病毒复制的快速反弹。在缺乏能够治愈艾滋病毒感染的可扩展治疗的情况下，抗逆转录病毒治疗是一种终身治疗，在成本和临床安全性方面构成了重大挑战。出于这些原因，根除或至少在功能上治愈艾滋病毒感染将对全球健康产生显著影响。在抗逆转录病毒疗法下，残留的炎症可能通过几种机制促进艾滋病毒的持久性，包括驱动维持宿主持久性的敏感细胞的感染，以及艾滋病毒特异性抗病毒免疫反应的耗尽。因此，可能会触发一种恶性循环，在这种恶性循环中，残留炎症、无效的抗病毒免疫反应和艾滋病毒持久性密切相关。因此，人们达成了强烈的共识，即仅通过强化抗逆转录病毒疗法无法治愈艾滋病毒感染，可能需要旨在限制残余炎症和改善抗病毒免疫反应的新方法。该项目的首要目标是探索一种新型的联合白介素21和干扰素-a(IFNA)干预治疗SIV感染的恒河猴(RMS)的治疗潜力。我们认为，IL-21和IFNA的序贯给药是安全的，并将通过减少免疫功能障碍和炎症(通过IL-21)，以及增强一些宿主限制因子(通过IFNA)介导的抗病毒功能，对HIV持久性具有很强的协同作用。这些假说将在AIMS 1和AIMS 2中得到验证。此外，我们还提出了一系列机制研究，旨在确定IL-21和IFNA序贯给药的分子和细胞效应[AIMS 3]。如果我们的假设是正确的，拟议的研究将提供体内证据，表明在HIV感染的最相关的临床前动物模型中，连续使用IL-21和IFNA治疗后，炎症减轻、免疫功能改善和病毒库减少，并使用两种分子作为单一药物，正在测试(IL-21)或被FDA批准(IFNA)用于治疗几种人类疾病。如果成功，建议的基于免疫的干预将在人体临床试验中进行测试，以评估其作为治疗艾滋病毒感染的功能性疗法的潜力。