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

描述(由申请人提供)：阐明宿主先天抗病毒效应机制，在感染的最早阶段控制进入部位的艾滋病毒-1复制可能有助于开发有效的艾滋病疫苗。我们的实验室在实现这一目标方面取得了重大进展，证明了传播的方正(TF)病毒穿过黏膜并引发生产性全身感染，比在慢性感染期间占主导地位的病毒对1型干扰素(IFN)的抗病毒作用的抵抗力要强得多(Parrish等人，PNAS，2013；Fenton-May等人，提交)。这些发现表明，由1型IFN上调的抗病毒基因对传播的HIV-1池施加了显著的选择压力，导致通过相对抗干扰素的变种建立系统感染。在这项应用中，我们建议通过鉴定干扰素刺激的抗病毒药物来利用这一发现 通过确定这些新发现的效应机制是否可以被用于疫苗设计，来确定在进入部位对抗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取和初始传播的新干预措施。我们已经建立了一种新的基于病毒的方法，它将使我们能够通过表征涉及的特定干扰素刺激基因(ISGs)以及赋予其活性抵抗力的TF病毒决定因素来剖析导致粘膜早期“抗病毒状态”的因素。具体目标是：1.量化1型干扰素耐药性对HIV-1传播适合度的贡献。2.定位传播的方正病毒对1型干扰素耐药的病毒决定因素。3.鉴定在HIV-1感染早期对其施加抗病毒压力的干扰素刺激基因(ISGs)。4.比较不同疫苗接种方案诱导抗病毒ISG的能力 在HIV-1早期控制中发挥重要作用。我们期待这些研究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，这些机制控制HIV-1在传播地点或附近的复制，在病毒最脆弱的时候立即在暴露后的几个小时和几天发挥作用。

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.