Innate Immune Surveillance of HIV-1 During Transmission and Systemic Infection

HIV-1 在传播和全身感染过程中的先天免疫监视

• 批准号: 9345240
• 负责人: SUMIT K CHANDA
• 金额: $ 91.01万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-28 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9345240
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adjuvant; Animals; Antigen Presentation; Antiviral Agents; Binding; Biochemical; Biochemical Genetics; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; Data; Dendritic Cells; Development; Disease; Environment; Event; Gatekeeping; Genes; Genetic Transcription; Genome; Growth Factor; HIV; HIV Infections; HIV vaccine; HIV-1; Hybrids; Immune; Immune response; Immunologic Surveillance; Infection; Infection prevention; Innate Immune Response; Interferons; Lighting; Mediating; Microbe; Modeling; Molecular; Mucous Membrane; Mutagenesis; Myeloid Cells; Nucleic Acids; Pathway interactions; Pattern; Pattern recognition receptor; Peripheral; Post-Translational Protein Processing; Process; Production; Publishing; RNA Interference; Regulation; Reporting; Role; Series; Sexual Transmission; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Structure; System; Systemic infection; Vaccine Adjuvant; Viral; Viral Proteins; Virus; base; cytokine; design; helicase; in vivo; microbial; mutant; network models; novel; novel strategies; novel therapeutic intervention; novel vaccines; pathogen; reconstitution; response; sensor; success; surveillance network; tool; transmission process; treatment strategy; vaccination strategy

Project Summary Innate immune responses represent one of the first and most potent lines of defense against infection. Importance of this surveillance network is underscored by the numerous mechanisms that pathogens have evolved to counteract and evade these responses. The success of the immediate innate immune response relies on the recognition of conserved structures, termed pathogen associated molecular patterns (PAMPs), commonly present in microbes but not in the host. Pattern recognition receptors (PRRs) act as microbial sensors for the host. The sensing of PAMPs by host PRRs initiate the induction of several intracellular signaling events, triggering the expression of cytokines and interferons, which can govern potent restrictors of pathogen infection. In this application, we propose to pursue the hypothesis that a robust innate immune recognition and response to HIV-1 exposure, likely elicited from abortive infection of myeloid cells, rises from the activation of key pattern recognition receptor (PRR) pathways and results in a localized antiviral environment that markedly decreases the likelihood of CD4+ T cell infection and subsequent spread of infection, both in the mucosa and during peripheral infection. The cGAS cytoplasmic DNA sensing pathway, which is particularly active in myeloid cells, has recently been identified as a key sensor for reverse transcribed HIV-1 DNA. Activation of this and potentially other PRR-governed pathways promote the secretion of interferons (IFNs) leading to the transcription of hundreds of interferon-stimulated genes (ISGs), some of which contribute to suppression of HIV-1 replication. Recently, we have reported the identification PQBP1 as a critical component in the recognition of early HIV-1 nucleic acid products required for activation of the cGAS DNA sensing pathway, resulting IFN induction in HIV-infected myeloid cells. Here, we propose to investigate in more detail the regulation of this novel sensing circuit, including understanding the features and accessibility of the HIV-1 PAMP, its downstream regulation, and its impact in HIV-1 transmission. A better understanding of the innate response circuitry that senses HIV-1 infection is likely to enable the development of novel therapeutic interventions against systemic HIV-1 infection, and the illumination of the molecular basis of a protective mucosal innate response to HIV-1 will be critical in next generation vaccine and adjuvant design.

项目摘要 先天免疫反应是抵抗感染的第一道也是最有效的防线之一。 病原体具有的多种机制强调了这一监测网络的重要性 进化来抵消和逃避这些反应。即刻先天免疫反应的成功 依赖于保守结构的识别，称为病原体相关分子模式（PAMP）， 通常存在于微生物中，但不存在于宿主中。模式识别受体（PRRs）作为微生物 主机的传感器。宿主PRR对PAMPs的感应启动了几种细胞内的诱导， 信号事件，触发细胞因子和干扰素的表达，这可以控制有效的限制因子， 病原体感染在本申请中，我们提出了一个假设，即一个强大的先天免疫系统， 对HIV-1暴露的识别和反应，可能是由骨髓细胞的流产感染引起的， 关键模式识别受体（PRR）途径的激活，并导致局部抗病毒 环境，显着降低CD 4 + T细胞感染的可能性和随后的传播， 感染，无论是在粘膜和外周感染。cGAS细胞质DNA传感途径， 在骨髓细胞中特别活跃，最近被鉴定为逆转录酶的关键传感器。 HIV-1 DNA这种和潜在的其他PRR调控途径的激活促进了 干扰素（IFN）导致数百个干扰素刺激基因（ISG）的转录，其中一些 有助于抑制HIV-1的复制。最近，我们报道了鉴定PQBP 1作为一个关键的 识别cGAS DNA激活所需的早期HIV-1核酸产物的组分 感应途径，导致HIV感染的骨髓细胞中的IFN诱导。在这里，我们建议调查更多 详细介绍了这种新型传感电路的调节，包括了解的特点和可访问性， HIV-1 PAMP，其下游调节及其在HIV-1传播中的影响。更好地理解 感知HIV-1感染的先天反应回路可能使新的治疗药物的开发成为可能。 针对系统性HIV-1感染的干预措施，以及对保护性HIV-1感染的分子基础的阐明， 粘膜对HIV-1的先天反应在下一代疫苗和佐剂设计中将至关重要。