Innate Immunity and HIV Restriction

我们假设，在项目1中确定的几个因素作为HIV复制的限制因素将是宿主抗病毒传感机制和/或该传感机制下游途径的组成部分。限制性因素可包括导致抗病毒应答的抗病毒传感机制的已知和未知刺激物。已知有四个家族的病毒病原体的感应分子诱导IFN和/或抗病毒应答，其中两个是细胞质外受体，Toll样受体（TLR）和凝集素样受体（LLR），另外两个是细胞质受体，Nod样受体（NLR）和RlG-1样受体（RLR）。然而，关于HIV如何与这些传感途径相互作用并诱导和/或抑制抗病毒应答，例如诱导具有抗HIV活性的IFN和/或IFN刺激基因（ISG），知之甚少。我们建议确定进入这些途径的限制因素以及它们在细胞水平上抗HIV先天免疫应答中所起的作用。此外，我们将研究这些途径在HIV感染过程中的分子调控及其在HIV抗病毒反应中的影响。尽管I型IFN具有公认的抗病毒活性，但仅鉴定了介导IFN对HIV复制的抑制作用的少数特异性因子。在与项目1、3、4和6合作的同时，我们将生成包括本PPG中鉴定的限制因子的HIV-1先天免疫途径激活图谱，我们还将选择IFN诱导的4-5种特异性限制因子，以更详细地研究其抗HIV-1活性。为了实现这些目标，我们组建了一个由三名在这些先天免疫途径方面具有丰富经验的合作研究者组成的团队，他们将负责实现以下具体目标。Garcia-Sastre博士在IFN和RLR途径及其在病毒感染期间的调节方面拥有超过12年的经验。大卫博士已经研究干扰素系统18年了，他的实验室发现了通过病毒感染和TLR连接激活IRF-3作为关键的先天免疫应答途径。Reed博士是NLR信号传导领域的领导者。所产生的数据将有助于提高对HIV与先天免疫系统相互作用的理解，并将确定可能作为开发治疗策略的未来目标的抗病毒反应的新型调节剂。

We hypothesize that several of the factors identified in Project 1 as restriction factors of HIV replication will be components of the host antiviral sensing machinery and/or of pathways downstream this sensing machinery. Restriction factors may include known and unknown stimulators of the antiviral sensing machinery leading up to the antiviral response. There are four known families of sensing molecules of viral pathogens that induce IFN and/or antiviral responses, two of them are extracytoplasmic receptors, the Tolllike receptors (TLR) and the lectin-like receptors (LLR), and the two other are cytoplasmic receptors, the Nod-like receptors (NLR) and the RlG-1-like receptors (RLR). However, very little is known about how HIV interacts with these sensing pathways and induces and/or represses an antiviral response such as the induction of IFN and/or IFN-stimulated genes (ISGs) with anti-HIV activity. We propose to determine the restriction factors that feed into these pathways and the role they play in the anti-HIV innate immune response at the cellular level. In addition, we will study the molecular regulation of these pathways during HIV infection and their impact in the HIV antiviral response. Despite the recognized antiviral activity of type I IFN, only a few specific factors that mediate the inhibitory effect of IFN on HIV replication have been identified. While in collaboration with Projects 1, 3, 4 and 6 we will generate an HIV-1 innate immune pathway activation map that includes the restriction factors identified in this PPG, we will also select 4-5 specific restrictions factors induced by IFN to study in more detail their anti-HIV-1 activities. To achieve these goals, we have assembled a team of three co-investigators with extensive experience in these innate immunity pathways who will be responsible for accomplishing the specific aims below. Dr. Garcia-Sastre has more than 12 years of experience in IFN and the RLR pathways, and their modulation during viral infection. Dr. David has been working with the interferon system for 18 years, and his lab discovered the activation of IRF-3 by virus infection and TLR ligation as a key innate immune response pathway. Dr. Reed is a leader in the area of NLR signaling. The generated data will aide in improving understanding of the interactions of HIV with innate immune systems, and will identify novel regulators of antiviral responses that may serve as future targets for developing therapeutic strategies.