Innate Immunity and HIV Restriction

我们假设，在项目1中被确定为HIV复制限制因素的几个因素将是宿主抗病毒传感机制和/或该传感机制下游通路的组成部分。限制因素可能包括导致抗病毒反应的抗病毒传感机制的已知和未知刺激物。已知的病毒病原体感应分子有四个家族，其中两个是胞外受体，即Tolllike受体(TLR)和凝集素样受体(LLR)，另两个是细胞质受体，即Nod样受体(NLR)和RLG-1样受体(RLR)。然而，关于HIV如何与这些感知通路相互作用以及如何诱导和/或抑制抗病毒反应，如诱导干扰素和/或具有抗HIV活性的干扰素刺激基因(ISGs)，人们知之甚少。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先天免疫反应中所起的作用。此外，我们还将研究这些途径在HIV感染过程中的分子调控以及它们在HIV抗病毒反应中的影响。尽管已知I型干扰素的抗病毒活性，但只有少数几个特定因素介导了干扰素对艾滋病毒复制的抑制作用。虽然我们将与项目1、3、4和6合作生成包含PPG中确定的限制因素的HIV-1天然免疫途径激活图，但我们也将选择4-5个由干扰素诱导的特定限制因素，以更详细地研究它们的抗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拥有丰富经验的联合调查人员组成的团队，他们将负责实现以下具体目标。Garcia-Sastre博士在干扰素和RLR途径及其在病毒感染过程中的调控方面拥有12年以上的经验。大卫博士从事干扰素系统的研究已有18年，他的实验室发现，通过病毒感染和TLR结扎激活IRF-3是一条关键的先天免疫反应途径。里德博士是NLR信令领域的领导者。生成的数据将有助于提高对艾滋病毒与先天免疫系统相互作用的理解，并将确定可能作为未来治疗策略开发目标的抗病毒反应的新调节器。

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.