Limiting HIV establishment and maintenace by preserving intestinal immunity

通过保护肠道免疫力来限制艾滋病毒的建立和维持

• 批准号: 9349159
• 负责人: Siddappa N Byrareddy
• 金额: $ 84.77万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349159
• 关键词: Acute; Animal Model; Animals; Anti-Retroviral Agents; Antiviral Agents; Antiviral Response; Automobile Driving; Biological Assay; Blood; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Chronic; Clinical Trials; Colitis; Combined Modality Therapy; Comorbidity; Data; Data Set; Defensins; Detection; Development; Disease Progression; Disease remission; Drug Kinetics; Epithelial; FDA approved; Genetic Transcription; Goals; HIV; HIV Infections; Homing; Human; Immune; Immune System Diseases; Immune System and Related Disorders; Immune response; Immune system; Immunity; Immunologics; Individual; Infection; Inflammation; Interruption; Intervention; Intestines; Longevity; Lymphoid Tissue; Macaca mulatta; Maintenance; Malignant Neoplasms; Molecular; Monoclonal Antibodies; Plasma; Pre-Clinical Model; Publishing; Quality of life; Regulatory T-Lymphocyte; Research; Residual Tumors; Residual state; Route; SIV; Safety; Series; Site; Supplementation; T-Lymphocyte; Testing; Therapeutic; Tight Junctions; Time; Tissues; Viral; Viral Load result; Viral reservoir; Virus; Virus Latency; Virus Replication; Work; animal resource; base; clinically relevant; effective therapy; experience; gastrointestinal; immune activation; immune function; improved; in vivo; integrin alpha4beta7; interleukin-21; lymph nodes; mortality; novel; pre-clinical; premature; receptor; reconstitution; safety testing; senescence; viral rebound; virology

Despite the development of potent anti-retroviral therapy (ART) that effectively suppresses virus replication in the majority of HIV-infected individuals, a treatment capable of curing this infection is still not available. Residual disease in ART-treated, HIV-infected individuals consists mainly of (i) persistent inflammation, limited CD4+ T cell reconstitution, and premature immune senescence, 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 interrupted. Gut is the first major site where HIV infection and replication takes place, with CD4+ T cells that express the co-receptor CCR5 and the heterodimeric gastrointestinal tissue (GIT) homing molecule α4β7 integrin serving as the major target. Indeed, HIV infection is associated with a profound loss of mucosal immunological and physical integrity, which is considered a key cause of inflammation during HIV infection. Importantly, inflammation may critically contribute to HIV persistence by several mechanisms: driving the infection of susceptible cells that sustain the persistence of the reservoir; up-regulating the expression of co-inhibitory receptors, which contribute to the persistence of latently infected cells; and limiting the function of HIV-specific immune responses that could potentially clear the virus. Therefore, developing strategies aimed at limiting inflammation and improving immune responses especially in the gut and other lymphoid tissues may critically impact on HIV persistence, and is a key priority for HIV research. The overarching goal of this project is to explore the therapeutic potential of a novel, combined Interleukin (IL)-21 and anti-α4β7 intervention in ART-treated, SIV-infected rhesus macaques (RMs). Based on an exciting set of data we recently generated in separate studies that utilized IL-21 or anti-α4B7 interventions alone, we propose that IL- 21 supplementation of anti-α4β7 treatment will result in reduced immune dysfunction and inflammation (via IL-21) as well as in protection of gut from SIV infection and virologic control (via anti-α4β7). As such, we hypothesize that by targeting key contributors of HIV persistence, IL-21 supplementation of anti-α4β7 treatment will have a strong synergistic effect in the progressive reduction and potential elimination of the HIV reservoir. We are confident the proposed studies will provide in vivo evidence of reduced establishment (Aim 1) and maintenance (Aim 2) of the viral reservoir following combined IL-21 and anti-α4β7 treatment. This study will be conducted in the most relevant preclinical animal model of HIV infection and using two molecules that, as a single agent, are being tested for cancer (IL-21) or approved by the FDA for treatment of IBD and colitis (anti- α4β7). Moreover, we are proposing a series of mechanistic studies aimed at defining the molecular and cellular effects of the proposed intervention. If successful, the proposed immune-based intervention would inform human clinical trials aimed at functionally curing HIV infection. Thus, we believe that the proposed studies are of high and immediate significance to the field of HIV cure research.

尽管开发了有效的抗逆转录病毒疗法（ART），可以有效抑制病毒复制 对于大多数艾滋病毒感染者来说，仍然没有能够治愈这种感染的治疗方法。 接受 ART 治疗的 HIV 感染者的残留疾病主要包括 (i) 持续性炎症、有限的炎症 CD4+ T 细胞重建和过早的免疫衰老，以及 (ii) 持久性储存库的存在 不受 ART 影响且导致病毒快速反弹的潜伏感染细胞 如果 ART 中断，则进行复制。肠道是艾滋病毒感染和复制发生的第一个主要场所， 表达共受体 CCR5 和异二聚体胃肠组织 (GIT) 归巢的 CD4+ T 细胞 分子α4β7整合素作为主要靶标。事实上，艾滋病毒感染与生命力的严重丧失有关。 粘膜免疫和物理完整性，被认为是 HIV 期间炎症的关键原因 感染。重要的是，炎症可能通过多种机制对 HIV 持续存在产生重要影响： 维持病毒库持续存在的易感细胞的感染；上调表达 共抑制受体，有助于潜伏感染细胞的持续存在；并限制其功能 艾滋病毒特异性免疫反应可能会清除病毒。因此，制定旨在 限制炎症和改善免疫反应，特别是在肠道和其他淋巴组织中可能 严重影响艾滋病毒的持久性，是艾滋病毒研究的一个关键优先事项。本次活动的总体目标是 该项目旨在探索一种新型联合白细胞介素 (IL)-21 和抗 α4β7 的治疗潜力 对接受 ART 治疗、感染 SIV 的恒河猴 (RM) 进行干预。基于一组令人兴奋的数据，我们 最近在单独使用 IL-21 或抗 α4B7 干预措施的单独研究中得出，我们建议 IL- 21 补充抗α4β7治疗将减少免疫功能障碍和炎症 （通过 IL-21）以及保护肠道免受 SIV 感染和病毒学控制（通过抗 α4β7）。作为 因此，我们假设通过针对 HIV 持续存在的关键因素，补充抗 α4β7 的 IL-21 治疗将对逐步减少和潜在消除艾滋病毒产生强大的协同效应 水库。 我们相信，拟议的研究将提供减少定植的体内证据（目标 1）和 IL-21 和抗 α4β7 联合治疗后病毒库的维持（目标 2）。这项研究将 在最相关的 HIV 感染临床前动物模型中进行，并使用两种分子作为 单一药物，正在接受癌症测试 (IL-21) 或经 FDA 批准用于治疗 IBD 和结肠炎（抗- α4β7)。此外，我们提出了一系列机制研究，旨在定义分子和细胞 拟议干预措施的影响。如果成功，拟议的基于免疫的干预措施将告知 旨在功能性治愈艾滋病毒感染的人体临床试验。因此，我们认为所提出的研究是 对艾滋病毒治疗研究领域具有高度和直接的意义。