Role of TLR3 pathway in HIV infection

寄主生物体对入侵病原体的快速识别是建立有效免疫的关键 回应。病原体上的保守结构特征称为PAMP，由Toll样细胞识别 表面受体，这是进化保守的天然免疫系统的一部分。十多年前，我们 共同发现TLR配体对干扰素调节因子3(IRF3)的激活以及随后的诱导 其中，I型干扰素基因(干扰素α/β)和干扰素刺激基因(ISGs)。我们随后 描述了参与TLR介导的IRF3和IRF7激活的多种成分及其在这两个过程中的作用 先天免疫和获得性免疫。 令人信服的证据表明，逆转录病毒感染后早期的免疫学事件是至关重要的。 例如，影响艾滋病毒/艾滋病病程的决定因素。先天免疫反应是一种 古代防御系统由功能不同的子系统组成，这些子系统已经进化成对抗感染的 微生物病原体，包括艾滋病毒等逆转录病毒。先天免疫反应不是抗原特异性的， 它由PAMP/TLR诱导的干扰素系统和基于细胞的抗病原体组成 限制病原体复制的对策。了解先天免疫反应和 促进或限制HIV感染不同步骤的动力学的途径对于设计新的 在这些传染病过程中进行治疗干预的药理学策略，以开发 诊断工具或预防感染。 目前关于TLR3及其下游信号转导元件TRIF、TBK1和 IRF3/7告诉我们，在病毒感染期间激活这一途径会导致I型干扰素的产生， 这反过来又通过上调ISGs来调节它们的抗病毒活性。因此，这条路径被认为是 是防御RNA病毒的基石，包括艾滋病毒等逆转录病毒。因此，这是一次引人注目的 而意想不到的发现，TLR3，TRIF或IRF7的消融导致艾滋病毒感染的显著减少，相反 而不是增强功能。同样，对TBK1或新发现的Polo样激酶的药理抑制， 以及p300废除了艾滋病毒复制周期的完成。有趣的是，我们发现 一旦病毒cDNA整合到宿主细胞中，TLR3-&GT；IRF7途径的中断就不重要了 基因组。这些观察结果使我们得出假设，IRF7激活在TLR3/TRIF下游 促进病毒cdna的生成、稳定或整合，而药物抑制这一级联反应 在接触艾滋病毒后的非常早期阶段有可能防止建立病毒库 类似于RT或整合酶抑制剂，其好处是出现耐药性的可能性有限。

Rapid recognition of invading pathogens by the host organism is crucial in mounting an effective immune response. Conserved structural features on pathogens termed PAMPs are recognized by the Toll-like cell surface receptors, which are part of the evolutionary conserved innate immune system. Over a decade ago we co-discovered the activation of Interferon Regulatory Factor 3 (IRF3) by TLR ligands, and the ensuing induction of both, type I interferon genes (IFNα/β) and Interferon Stimulated Genes (ISGs). We subsequently characterized many components involved in TLR-mediated IRF3 and IRF7 activation and their role in both innate and adaptive immunity. Compelling evidence indicates that immunological events early after retroviral infection are critical determinants shaping the course of, for instance, HIV/AIDS disease. The innate immune response is an ancient defense system made up of functionally distinct subsystems that have evolved to counter infection by microbial pathogens including retroviruses such as HIV. The innate immune response is not antigen-specific, and is composed of the PAMP/TLR-induced interferon (IFN) system as well as cell-based anti-pathogen countermeasures that restrict the replication of pathogens. Understanding the innate immune response and the pathways that promote or restrict the kinetics of different steps of HIV infection is essential for devising novel pharmacological strategies for therapeutic intervention during these infectious disease processes, to develop diagnostic tools or to prevent infection. The current paradigm of the role of TLR3 and its downstream signaling components TRIF, TBK1 and IRF3/7 teaches that activation of this pathway during viral infection leads to the production of type I interferons, which in turn mediate their antiviral activity via the upregulation of ISGs. As such, this pathway is considered a cornerstone in the defense against RNA viruses, including retroviruses such as HIV. It was therefore a striking and unexpected finding that ablation of TLR3, TRIF or IRF7 lead to a dramatic reduction in HIV infection, rather than an enhancement. Similarly, pharmacological inhibition of TBK1, or the newly implicated polo-like kinases, as well as p300 abolished the completion of the HIV replication cycle. Interestingly, we found that the disruption of the TLR3->IRF7 pathway did not matter once the viral cDNA was integrated into the host cell genome. These observations lead us to the hypothesis that IRF7 activation downstream of TLR3/TRIF promotes generation, stability or integration of the viral cDNA, and that pharmacological inhibition this cascade at the very early stage after exposure to HIV has the potential to prevent the establishment of a viral reservoir similar to RT or integrase inhibitors, with the benefit of a limited likelihood of the emergence of drug resistance.