Targeting SIV reservoirs with type I Interferons

 描述：尽管艾滋病研究取得了许多重大进展，包括开发了抑制病毒复制的抗逆转录病毒药物，并极大地降低了艾滋病毒感染的死亡率和发病率，但仍然没有治愈感染的治疗方法。的确， 联合抗逆转录病毒治疗(ART)必须终身进行，因此在成本和临床安全性方面构成了巨大的挑战，而且中断治疗会导致大多数艾滋病毒感染者的病毒血症迅速反弹。为此，需要新的方法来根除潜伏感染细胞的储存库，这些细胞在抗逆转录病毒治疗期间持续存在，是 当治疗中断时，病毒重新激活的来源。这项建议的主要目的是探索I型干扰素(干扰素-I)的治疗潜力，它能激活一个非常强大的天然抗病毒分子系统，减少持续存在的病毒感染细胞的储备库。 在艺术之下。在这项赠款申请的R21阶段，我们建议使用现有的、已建立的猕猴SIVmac感染(Rms)非人类灵长类动物模型，在相对较小的先导研究中，评估聚乙二醇化干扰素-α2a(pIFN-α2a)的潜在影响。 经ART治疗、SIV感染的RMS中潜伏感染细胞储存库的总体大小、解剖位置和细胞分布。我们将使用这个非常强大的模型来直接在体内和多个器官(即血液、淋巴结、脾、粘膜组织等)中进行研究。以及细胞类型(即记忆CD4T细胞亚群和巨噬细胞)是否以及在多大程度上给予pIFN-α2a增强了ART对病毒库的影响。在本申请的R21部分建议的研究结果将为在本建议的R33阶段进行的进一步实验铺平道路，在该实验中，我们将在接受长期ART治疗并显示完全抑制病毒复制的SIV感染的RMS的更大队列中，测试连续两个周期的pIFN-α2a治疗对(I)潜伏感染细胞持续储存库的大小，以及(Ii)ART中断后血浆病毒血症反弹的时间的影响。我们相信，拟议的研究将对I型干扰素在减少和/或改变细胞和解剖分布中的作用提供前所未有的见解。 在致病性慢病毒感染的体内模型中，潜伏感染细胞的持续病毒库，在该模型中，主动病毒复制被ART完全抑制。我们相信，这些结果将对确定HIV感染者接受干扰素-I治疗的潜力至关重要。

 DESCRIPTION: Despite many major advances in AIDS research, including the development of anti-retroviral drugs that suppress virus replication and greatly reduce the mortality and morbidity of HIV infection, a treatment that can cure the infection is still not available. Indeed, combination antiretroviral therapy (ART) must be taken for life, thus posing significant challenges in terms of costs and clinical safety, and interruption of therapy results in a rapid rebound of viremia in the majority of HIV-infected individuals. To this end, new approaches are required to eradicate the reservoirs of latently infected cells that persist during ART and are the source of virus reactivation when therapy is interrupted. The overarching Aim of this proposal is to explore the therapeutic potential of type I interferon (IFN-I), that activates a very potent natural antiviral molecular system, in reducing the reservoirs of virus-infected cells that persist under ART. In the R21 phase of this grant application we propose to use the existing, well-established nonhuman primate model of SIVmac infection of rhesus macaques (RMs) to evaluate, in a relatively small pilot study, the potential impact of pegylated IFN-α2a (pIFN-α2a) on the overall size, anatomic location, and cellular distribution of the reservoirs of latently infected cells in ART-treated, SIV-infected RMs. We will use this very robust model to investigate directly in vivo and in multiple organs (i.e., blood, lymph nodes, spleen, mucosal tissues, etc.) and cell types (i.e., memory CD4+ T cell subsets and macrophages) whether and to what extent pIFN-α2a administration enhances the effect of ART on the virus reservoir. The results of the studies proposed in the R21 part of this application will pave the way for further experiments, to be conducted in the R33 phase of this proposal, in which we will test, in a larger cohort of SIV-infected RMs treated with long-term ART and exhibiting full suppression of virus replication, the effect of two consecutive cycles of pIFN-α2a treatment on (i) the size of the persisting reservoirs of latently infected cells, and (ii) the time of rebound of plasma viremia afer ART interruption. We believe that the proposed studies will provide unprecedented insights into the role of type I interferon in reducing and/or altering the cellular and anatomic distribution of the persistent virus reservoirs of latently infected cells in an in vivo model of pathogenic lentivral infection in which active virus replication is fully suppressed by ART. We believe that these results will be crucial to determine the potential of IFN-I therapy in HIV-infected individuals.