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