Targeting SIV reservoirs with type I Interferons

 产品说明：尽管在艾滋病研究方面取得了许多重大进展，包括研制出了抑制病毒复制并大大降低艾滋病毒感染的死亡率和发病率的抗逆转录病毒药物，但仍然没有治愈这种感染的治疗方法。的确， 联合抗逆转录病毒疗法（ART）必须终身服用，因此在成本和临床安全性方面构成重大挑战，并且中断疗法导致大多数HIV感染者的病毒血症迅速反弹。为此，需要新的方法来根除在ART期间持续存在的潜伏感染细胞的储库， 治疗中断时病毒再激活的来源。本提案的首要目的是探索I型干扰素（IFN-I）的治疗潜力，其激活非常有效的天然抗病毒分子系统，以减少持续存在的病毒感染细胞的储存库 在本基金申请的R21阶段，我们建议使用现有的、建立良好的恒河猴（RM）SIVmac感染的非人灵长类动物模型，在相对较小的试点研究中评估聚乙二醇化IFN-α2a（pIFN-α2a）的潜在影响。 对ART治疗的SIV感染RM中潜伏感染细胞的总体大小、解剖位置和细胞分布的影响。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）和细胞类型（即，记忆性CD 4 + T细胞亚群和巨噬细胞）是否以及在何种程度上pIFN-α2a给药增强ART对病毒库的作用。在本申请的R21部分中提出的研究结果将为在本申请的R33阶段进行的进一步实验铺平道路，其中我们将在接受长期ART治疗并表现出病毒复制完全抑制的SIV感染RM的较大队列中进行测试，连续两个周期的pIFN-α2a治疗对（i）潜伏感染细胞的持续储存库的大小，和（ii）ART中断后血浆病毒血症反弹的时间的影响。我们相信，这些研究将为I型干扰素在减少和/或改变肿瘤细胞和解剖分布方面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，活性病毒复制被ART完全抑制，潜伏感染细胞的持久性病毒库。我们相信，这些结果对于确定IFN-I治疗HIV感染个体的潜力至关重要。

 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.