Restriction of HIV-1 transmission by type 1 interferons

描述(由申请人提供)：HIV-1粘膜感染的特点是在最初进入的部位迅速诱导1型干扰素(IFN)。然而，这些细胞因子在感染的最早阶段控制HIV-1复制的程度以及它们对传播瓶颈的贡献尚不清楚。我们最近发现，传播的方正(TF)病毒已经穿过粘膜并启动了有效的全身感染，与在慢性HIV-1感染期间占主导地位的病毒相比，对1型IFN的抗病毒作用显著更强(1，2)。这些发现强烈表明，在感染的最早阶段，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。在这一应用中，我们建议利用这一观察结果，通过鉴定干扰素刺激的抗病毒基因在进入部位对抗HIV-1复制，并确定这些效应机制是否可以被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，了解在感染的最早阶段控制HIV-1的宿主抗病毒效应机制将导致新的干预措施，这些干预措施能够削弱病毒的获得和最初的传播，并可能具有治疗作用。我们已经建立了一种新的基于病毒的方法，该方法将使我们能够剖析1型IFN对粘膜早期“抗病毒状态”的贡献，并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。具体目标是：1.量化1型干扰素耐药性对HIV-1传播适合性的影响。2.检测不同1型干扰素亚型对HIV-1传播的抑制作用。3.定位传播的方正病毒对1型干扰素耐药的病毒决定因素。4.确定在HIV-1感染早期对HIV-1施加选择性压力的干扰素刺激基因(ISGs)。我们期望这些研究揭示1型干扰素是否有能力消除进入粘膜部位的病毒复制，并确定介导这一重要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.