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.

尽管发展了潜在的抗逆转录病毒疗法（ART），从而有效地抑制了病毒复制 大多数受HIV感染的人，能够治愈这种感染的治疗方法仍然无法使用。 ART治疗，感染HIV感染的个体中的残留疾病主要由（i）持续感染，有限 CD4+ T细胞重建和过早免疫，以及（ii）存在持续的储层 不受艺术影响并导致病毒快速反弹的潜在感染细胞 复制如果中断艺术。肠道是第一个发生艾滋病毒感染和复制的主要地点， 表达共受体CCR5和异二聚体胃肠道组织（GIT）归位的CD4+ T细胞 分子α4β7整联蛋白是主要靶标。实际上，艾滋病毒感染与深远的丧失有关 粘膜免疫和身体完整性，这被认为是艾滋病毒期间炎症的关键原因 感染。重要的是，感染可能会通过几种机制严重促进HIV的持久性：驾驶 维持储层持久性的易感细胞的感染；上调的表达 共抑制受体，这有助于延伸受感染细胞的持久性；并限制 HIV特异性免疫反应可能会清除病毒。因此，制定针对的策略 限制炎症并改善免疫反应，尤其是在肠道和其他淋巴组织中 对艾滋病毒的持久性产生严重影响，是艾滋病毒研究的关键重点。总体目标 项目是探索新颖的白介素（IL）-21和抗α4β7的治疗潜力 干预经过艺术治疗的SIV感染的恒河猕猴（RMS）。基于一组令人兴奋的数据 最近在单独使用IL-21或抗α4B7干预措施的单独研究中生成的，我们提出IL- 21补充抗α4β7治疗将导致免疫功能障碍和炎症减少 （通过IL-21）以及肠道免受SIV感染和病毒学对照（通过抗α4β7）的保护。 这样，我们假设通过靶向HIV持久性的关键因素，IL-21补充抗α4β7 治疗将对艾滋病毒的进行性减少和潜在消除具有很强的协同作用 水库。 我们有信心拟议的研究将为体内提供减少建立的证据（AIM 1）和 IL-21和抗α4β7处理后，病毒储量的维持（AIM 2）。这项研究将是 在最相关的HIV感染临床前动物模型中进行的，并使用两个分子作为A 单一药物正在接受癌症测试（IL-21）或FDA批准用于治疗IBD和结肠炎（抗 - α4β7）。此外，我们提出了一系列旨在定义分子和细胞的机械研究 拟议干预的影响。如果成功，拟议的基于免疫的干预将告知 人类临床试验旨在在功能上治愈HIV感染。那就是我们认为拟议的研究是 对艾滋病毒治疗研究领域具有高度和直接的意义。