Role of Type I IFNs in Mucosal HIV-1 Immunity and Pathogenesis

I 型干扰素在粘膜 HIV-1 免疫和发病机制中的作用

• 批准号: 9915855
• 负责人: Mario Luis Santiago
• 金额: $ 54.99万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915855
• 关键词: Acute; Antiviral Agents; Antiviral Therapy; Apoptosis; Automobile Driving; Biological; Biology; Biopsy; Blood; CCR5 gene; CD4 Positive T Lymphocytes; Cataloging; Catalogs; Cell Death; Cell physiology; Cells; Cessation of life; Chronic; Clinical; Data; Dendritic Cells; Development; Disease; Disease Progression; Enteral; Epithelial; Epithelium; Equilibrium; Exposure to; Feedback; Functional disorder; Gastrointestinal tract structure; Genes; Gram-Negative Bacteria; Gut Mucosa; HIV; HIV-1; IFNAR1 gene; Immune; Immunity; Individual; Infection; Inflammation; Innate Immune Response; Interferon Type I; Interferon-alpha; Interferons; Intervention; Intestines; Kinetics; Knowledge; Lamina Propria; Licensing; Link; Mediating; Microbe; Mitogens; Modeling; Mononuclear; Mucous Membrane; Myelogenous; Natural Immunity; Pathogenesis; Pathogenicity; Pathologic; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Prevotella; Production; Property; Proteomics; RNA; Regulation; Reporting; Role; SIV; Sampling; Signal Transduction; Site; Source; Subfamily lentivirinae; T-Cell Depletion; T-Cell Proliferation; T-Lymphocyte; Testing; Tissues; Transactivation; Transcript; acute infection; adaptive immunity; antiretroviral therapy; base; chronic infection; commensal bacteria; cytokine; dysbiosis; gene induction; genetic signature; humanized mouse; immune activation; immunoregulation; in vivo; inflammatory marker; insight; interferon alpha-1; microbial; microbiome; microbiota; next generation sequencing; novel; pleiotropism; prevent; recruit; response; transcriptomics

ABSTRACT The gut is a major site for early HIV-1 infection and CD4+ T cell depletion, and a critical compartment for the antiviral action of the type I interferons (IFN) that include the 12 IFNα subtypes and IFNβ. However, the initial IFN response may be suboptimal, as transmitted/founder (TF) HIV-1 strains still manage to break through. Using next-generation sequencing, we reported that the IFNα subtypes expressed by plasmacytoid dendritic cells (pDCs) following HIV-1 exposure ex vivo had relatively weak antiviral activity. These weakly antiviral IFNα subtypes include IFNα2, the only IFNα subtype approved for clinical use, and IFNα1, a potential antagonist of type I IFN signaling. To date, in-depth studies on the regulation and biological properties of the IFNα subtypes and IFNβ in primary pDCs and gut cells has not yet been undertaken. Paradoxically, the type I IFNs were also linked to chronic immune activation, a strong predictor of HIV-1 disease progression. The phenotype is likely due to the immunomodulatory properties of the type I IFNs, but the exact mechanisms remain unclear. Of note, gut barrier dysfunction occurs early in HIV-1 infection, leading to the translocation of microbes into the lamina propria, resulting in immune activation. We reported that gram-negative commensal bacteria enriched in the gut mucosa of HIV-1-infected individuals enhanced HIV-1 replication and CD4+ T cell death ex vivo in the gut Lamina Propria Aggregate Culture (LPAC) model. Here, we hypothesize that the transition from a protective to a pathogenic role for type I IFNs may be driven by translocating enteric microbes. Microbial exposure may raise the threshold for the antiviral effects of type I IFNs to manifest and `license' immunomodulatory ISGs to promote myeloid (mDC) activation/trans-infection and CD4+ T cell infection/ apoptosis. These microbe-driven pathogenic effects of type I IFNs may be sustained during chronic infection. Interestingly, we observed that type I IFN responses during chronic HIV-1 infection are compartmentalized in vivo, with differentially enhanced IFNα versus IFNβ in the blood versus the gut, respectively. To date, the cellular sources and mechanisms driving the elevated type I IFN signature in the gut remains unknown. We thus propose to investigate the role of type I IFNs in gut HIV-1 infection during the acute stage, at the onset of microbial translocation, and during the chronic stage. In Aim 1, we will evaluate the regulation, anti-HIV-1 activity and functional properties of the IFNα subtypes and IFNβ. In Aim 2, we will determine how type I IFNs modulate mDC activation and T cell function/survival in the context of HIV-1-associated gut dysbiosis and microbial translocation. In Aim 3, we will determine the source and triggers of abnormal type I IFN signature during chronic infection using gut tissues from uninfected, untreated HIV-1-infected and HIV-1-suppressed individuals. The results should provide urgently needed insights on how type I IFNs impact HIV-1 pathogenesis that may inform strategies to either harness these antiviral cytokines for curative strategies or block their immune effects to reduce chronic inflammation.

摘要 肠道是早期HIV-1感染和CD 4 + T细胞耗竭的主要部位，也是HIV-1感染的关键区室。 I型干扰素（IFN）的抗病毒作用，包括12种IFNα亚型和IFNβ。然而，最初 干扰素反应可能是次优的，因为传播/创始人（TF）HIV-1菌株仍然设法突破。 利用新一代测序技术，我们报道了由浆细胞样树突状细胞表达的IFNα亚型， 离体暴露HIV-1后的pDC细胞具有相对弱的抗病毒活性。这些弱抗病毒干扰素α 亚型包括IFNα2，唯一批准用于临床使用的IFNα亚型，和IFNα1，一种潜在的IFN α 1的拮抗剂。 I型IFN信号传导。迄今为止，关于IFNα亚型的调节和生物学特性的深入研究 和IFNβ在原代pDC和肠细胞中的作用尚未进行。巧合的是，I型IFN也是 与慢性免疫激活有关，这是HIV-1疾病进展的一个强有力的预测因素。表型很可能是 由于I型IFN的免疫调节特性，但确切的机制仍不清楚。值得注意的是， 肠道屏障功能障碍发生在HIV-1感染的早期，导致微生物移位到薄层中 固有的，导致免疫激活。我们报道了革兰氏阴性菌在大肠杆菌中富集， HIV-1感染者的肠道粘膜增强了肠道中HIV-1的体外复制和CD 4 + T细胞的死亡 固有层聚集体培养（LPAC）模型。在这里，我们假设从一个 I型IFN对致病作用的保护作用可能是由易位的肠道微生物驱动的。 微生物暴露可提高I型干扰素的抗病毒作用的阈值，以显示和“许可” 免疫调节ISG促进骨髓（mDC）活化/转感染和CD 4 + T细胞感染/ 凋亡I型IFN的这些微生物驱动的致病作用可在慢性感染期间持续。 有趣的是，我们观察到在慢性HIV-1感染期间I型IFN应答在以下区域被区室化： 体内，分别在血液和肠道中具有差异增强的IFNα和IFNβ。迄今为止 驱动肠中I型IFN信号升高的细胞来源和机制仍然未知。我们 因此，建议研究I型干扰素在肠道HIV-1感染的急性期，在发病时的作用。 微生物易位，以及在慢性阶段。在目标1中，我们将评估调节，抗HIV-1 IFNα亚型和IFNβ的活性和功能特性。在目标2中，我们将确定I型IFN 在HIV-1相关肠道生态失调的背景下调节mDC活化和T细胞功能/存活， 微生物易位在目标3中，我们将确定异常I型IFN特征的来源和触发因素 在慢性感染期间，使用来自未感染、未治疗的HIV-1感染者和HIV-1抑制者的肠道组织 个体这些结果应该为I型干扰素如何影响HIV-1发病机制提供迫切需要的见解 这可能会为利用这些抗病毒细胞因子进行治疗策略或阻断它们的治疗策略提供信息。 免疫效果，以减少慢性炎症。