Restriction of HIV-1 transmission by type 1 interferons

描述（由申请人提供）：HIV-1粘膜感染的特征是在初始进入部位快速诱导1型干扰素（ifn）。然而，这些细胞因子在感染的早期阶段控制HIV-1复制的程度及其对传播瓶颈的贡献尚不清楚。我们最近发现，与在慢性HIV-1感染中占主导地位的病毒相比，通过粘膜传播的创始病毒（TF）对1型ifn的抗病毒作用具有更强的抵抗力（1,2）。这些发现强烈表明，在感染的早期阶段，1型IFN上调的抗病毒基因对传播的HIV-1库施加了显著的选择压力，导致相对IFN耐药的变体建立全身性感染。在这项应用中，我们建议利用这一观察结果，鉴定干扰素刺激的抗病毒基因，这些基因在进入位点抑制HIV-1的复制，并确定这些效应机制是否可以用于设计新的预防和治疗策略来对抗HIV-1。我们的工作假设是，了解在感染的早期阶段控制HIV-1的宿主抗病毒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，并且也可能具有治疗效用。我们已经建立了一种新的基于病毒的方法，这将使我们能够解剖1型干扰素对粘膜早期“抗病毒状态”的贡献，并表征所涉及的特定干扰素刺激基因（isg），以及赋予其活性抗性的TF病毒决定因子。具体目标是：1。量化1型IFN耐药性对HIV-1传播适应度的影响。2. 研究不同1型IFN亚型限制HIV-1传播的潜力。3. 绘制在传播的创始病毒上赋予1型IFN抗性的病毒决定因子。4. 鉴定在感染早期阶段对HIV-1施加选择性压力的ifn刺激基因（ISGs）。我们希望这些研究能够揭示1型干扰素是否具有在进入粘膜部位消灭病毒复制病灶的能力，并确定介导这种重要的早期抗病毒活性的特定干扰素刺激基因（ISGs）。

DESCRIPTION (provided by applicant): Mucosal infection with HIV-1 is characterized by the rapid induction of type 1 interferons (IFNs) at the initial sites of entry. However, the extent to which these cytokines control HIV-1 replication during the earliest stages of infection and their contribution to the transmission bottleneck are not understood. We recently discovered that transmitted founder (TF) viruses that have crossed the mucosa and initiated a productive systemic infection are significantly more resistant to the antiviral effects of type 1 IFNs than viruses that predominate during chronic HIV-1 infection (1, 2). These findings strongly suggest that antiviral genes up-regulated by type 1 IFNs during the earliest stages of infection 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 t capitalize on this observation by identifying the IFN-stimulated antiviral genes that counteract HIV-1 replication at the site of entry and by determining whether these effector mechanisms can be exploited for the design of new prophylactic and therapeutic strategies to combat HIV-1. Our working hypothesis is that understanding the host antiviral effector mechanisms which control HIV-1 during the earliest stages of infection will lead to new interventions that are capable of impairing virus acquisition and initial spread, and may also have therapeutic utility. We have established a novel virus-based approach that will allow us to dissect the contribution of type 1 IFNs to the early "anti-viral state" in the mucosa and characterize 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 impact of type 1 IFN resistance on HIV-1 transmission fitness. 2. To examine the potential of different type 1 IFN subtypes to restrict HIV-1 transmission. 3. To map the viral determinants that confer type 1 IFN resistance on transmitted founder viruses. 4. To identify the IFN-stimulated genes (ISGs) that exert selective pressure on HIV-1 during the earliest stages of infection. We expect these studies to reveal whether type 1 IFNs have the capacity to extinguish foci of virus replication at the mucosal site of entry and to identify the particular interferon-stimulated genes (ISGs) that mediate this important early antiviral activity.