Harnessing type 1 IFN-stimulated antiviral mechanisms for HIV vaccine design

描述（由申请方提供）：阐明宿主先天性抗病毒效应器机制，该机制在感染的最早阶段控制HIV-1在进入部位的复制，这可能有助于开发有效的艾滋病疫苗。我们的实验室已经朝着这一目标取得了重大进展，证明了已经穿过粘膜并引发生产性全身感染的传播的创始者（TF）病毒比在慢性感染期间占优势的病毒对1型干扰素（IFN）的抗病毒作用具有显著更大的抗性（Parrish等人，PNAS，2013; Fenton-May等人，提交）。这些研究结果表明，1型干扰素上调的抗病毒基因对传播的HIV-1库施加了显着的选择性压力，导致建立系统性感染的变异，相对干扰素耐药。在本申请中，我们建议利用这一发现，通过鉴定干扰素刺激的抗病毒药物， 通过确定这些新发现的效应机制是否可以用于疫苗设计，来研究在进入位点抵抗HIV-1复制的基因。我们的工作假设是，了解在感染的最早阶段控制HIV-1的宿主效应机制将导致能够削弱病毒获得和初始传播的新干预措施。我们已经建立了一种新的病毒为基础的方法，将使我们能够解剖的因素，有助于早期的“抗病毒状态”的粘膜特征的特定干扰素刺激基因（ISG）参与，沿着TF病毒决定簇，赋予他们的活动阻力。具体目标是：1。量化1型干扰素耐药对HIV-1传播适应度的贡献。2.绘制赋予传播的创始者病毒1型IFN抗性的病毒决定簇。3.鉴定在感染早期阶段对HIV-1产生抗病毒压力的IFN刺激基因（ISG）。4.比较不同疫苗接种方案诱导抗病毒ISG的能力， 在早期HIV-1控制中发挥重要作用。我们希望这些研究能够为不同疫苗接种策略诱导抗病毒效应机制的能力提供重要的新见解，这些机制可以控制HIV-1在传播部位或附近的复制，在病毒最脆弱的暴露后的几小时和几天内立即发挥作用。

DESCRIPTION (provided by applicant): Elucidation of the host innate antiviral effector mechanisms that control HIV-1 replication at the site of entry during the earliest stages of infection could be instrumental for the development of an effective AIDS vaccine. Our laboratories have made significant progress toward this objective by demonstrating that transmitted founder (TF) viruses that have crossed the mucosa and initiated a productive systemic infection are considerably more resistant to the antiviral effects of type 1 interferons (IFNs) than viruses that predominate during chronic infection (Parrish et al., PNAS, 2013; Fenton-May et al., submitted). These findings suggest that antiviral genes up-regulated by type 1 IFNs exert significant selective pressure on the transmitted HIV-1 pool, resulting in the establishment of systemic infection by variants that are relatively IFN resistant. In this application, we propose to capitalize on this discovery by identifying the IFN-stimulated antiviral genes that counteract HIV-1 replication at the site of entry and by determining whether these newly-identified effector mechanisms can be harnessed for vaccine design. Our working hypothesis is that understanding the host effector mechanisms that control HIV-1 during the earliest stages of infection will lead to new interventions that are capable of impairing virus acquisition and initial spread. We have established a novel virus-based approach that will allow us to dissect the factors that contribute to the early "anti-viral state" in the mucosa by characterizing the particular interferon stimulated genes (ISGs) involved, along with the TF virus determinants that confer resistance to their activity. Specific Aims are: 1. To quantify the contribution of type 1 IFN resistance to HIV-1 transmission fitness. 2. To map the viral determinants that confer type 1 IFN resistance on transmitted founder viruses. 3. To identify the IFN-stimulated genes (ISGs) that exert antiviral pressure on HIV-1 during the earliest stages of infection. 4. To compare the ability of different vaccination regimes to induce antiviral ISGs that play an important role in early HIV-1 control. We expect these studies to provide important new insight into the capacity of different vaccination strategies to induce antiviral effector mechanisms that control HIV-1 replication at or near the site of transmission, acting in the hours and days immediately following exposure when the virus is most vulnerable.