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: 9450468
• 负责人: Siddappa N Byrareddy
• 金额: $ 82.94万
• 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/9450468
• 关键词: Acute; Animal Model; Animals; 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 response; Immune system; Immunity; Immunologics; Individual; Infection; Inflammation; Interruption; Intervention; Intestines; Longevity; Lymphoid Tissue; Macaca mulatta; Maintenance; Malignant Neoplasms; Molecular; Monoclonal Antibodies; Mucous Membrane; Plasma; Pre-Clinical Model; Publishing; Quality of life; Regulatory T-Lymphocyte; Research; Residual Tumors; Residual state; Route; SIV; Safety; Series; Site; Supplementation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tight Junctions; Time; Tissues; Viral; Viral Load result; Viral reservoir; Virus; Virus Latency; Virus Replication; Work; animal resource; antiretroviral therapy; 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.

尽管开发了有效抑制病毒复制的强效抗逆转录病毒疗法（ART）， 尽管大多数艾滋病毒感染者都患有艾滋病，但仍然没有能够治愈这种感染的治疗方法。 ART治疗的HIV感染者的残留疾病主要包括（i）持续性炎症，局限性炎症， CD 4 + T细胞重建和过早的免疫衰老，以及（ii）存在持久的水库 潜伏感染的细胞，不受ART的影响，并负责病毒的快速反弹 如果ART中断，则复制。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CCR 5和异二聚体胃肠组织（GIT）归巢的CD 4 + T细胞 分子α4β7整联蛋白作为主要靶标。事实上，艾滋病毒感染与严重的艾滋病毒感染有关。 粘膜免疫和物理完整性，这被认为是HIV感染期间炎症的关键原因 感染重要的是，炎症可能通过以下几种机制对艾滋病毒的持续性起关键作用： 易感细胞的感染，维持水库的持久性;上调表达 共抑制受体，其有助于潜伏感染细胞的持久性;以及限制 HIV特异性免疫反应，可能会清除病毒。因此，制定战略， 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， 这对艾滋病毒的持久性具有重要影响，是艾滋病毒研究的一个关键优先事项。这个项目的首要目标是 本研究旨在探索一种新型的联合白细胞介素（IL）-21和抗α4β7的治疗潜力， ART治疗的SIV感染恒河猴（RM）的干预。基于一组令人兴奋的数据， 最近在单独使用IL-21或抗-α 4 B7干预的单独研究中产生，我们提出IL-21和抗-α 4 B7干预可能与IL-21和抗-α 4 B7干预有关。 21补充抗α4β7治疗将导致免疫功能障碍和炎症减少 (via 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，我们假设通过靶向HIV持续存在的关键因素，IL-21补充抗α4β7 治疗将在逐步减少和潜在消除艾滋病毒方面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建立（目标1）的体内证据， IL-21和抗α4β7联合治疗后病毒库的维持（目的2）。本研究将 在HIV感染的最相关的临床前动物模型中进行，并使用两种分子， 单剂，正在测试癌症（IL-21）或FDA批准用于治疗IBD和结肠炎（抗- α4β7）。此外，我们提出了一系列的机制研究，旨在确定分子和细胞的 拟议干预的影响。如果成功，拟议的基于免疫的干预措施将为 人类临床试验旨在功能性治愈艾滋病毒感染。因此，我们认为拟议的研究是 对HIV治疗研究领域具有重要的现实意义。