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

项目摘要 先天免疫反应是抵御感染的第一道也是最有效的防线之一。 病原体具有的众多机制突显了这种监测网络的重要性。 进化来抵消和逃避这些反应。即刻先天免疫反应的成功 依赖于对保守结构的识别，称为病原体相关分子模式(PAMPs)， 通常存在于微生物中，但不存在于宿主中。模式识别受体(PRR)作为微生物 用于主机的传感器。宿主PRRs对PAMP的感知启动了几种细胞内PAMP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。在这个应用中，我们提出了一个假设，即一种强大的先天免疫 对HIV-1暴露的识别和反应，可能是由髓系细胞的流产感染引起的，从 关键模式识别受体(PRR)通路的激活导致局部抗病毒 显著降低CD4T细胞感染和随后传播的可能性的环境 感染，无论是在粘膜内还是在外周感染期间。CGAS细胞质DNA传感途径， 它在髓系细胞中特别活跃，最近被确定为逆转录的关键传感器 HIV-1DNA。激活这一途径和其他潜在的PRR控制的途径可以促进 干扰素(IFN)导致数百个干扰素刺激基因(ISGs)的转录，其中一些 有助于抑制艾滋病毒-1复制。最近，我们报告了PQBP1的鉴定为关键的 识别激活cGAS DNA所需的早期HIV-1核酸产物的成分 感应途径，导致在HIV感染的髓系细胞中诱导干扰素。在这里，我们建议在更多方面进行调查 详细介绍这一新型感测电路的调节，包括了解 HIV-1 PAMP、其下游调控及其在HIV-1传播中的影响。更好地理解 感知HIV-1感染的固有反应电路可能使开发新的治疗方法成为可能 针对系统性HIV-1感染的干预措施，以及保护性的分子基础的启发 粘膜对HIV-1的先天反应将是下一代疫苗和佐剂设计的关键。

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.