Regulation of the induction of IFNα subtypes during HIV infection

HIV 感染期间 IFNα 亚型诱导的调节

• 批准号: 318291924
• 负责人: Professor Dr. Ulf Dittmer
• 金额: --
• 依托单位: Institut für Virologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/318291924?language=en
• 关键词: Regulation; induction; IFN; subtypes; during

The gut-associated lymphoid tissue (GALT) is critical for the initial establishment and spread of HIV-1 infection. It is currently thought that type I interferons (IFNs), induced during host innate immune responses by various pattern recognition receptors, play a key role in counteracting initial viral spread. Type I IFNs are induced in early HIV-1 infection, and plasmacytoid dendritic cells, which produce type I IFNs in large quantities, are rapidly recruited to mucosal sites of infection. Type I IFNs likely inhibit HIV-1 by increasing the expression and activity of restriction factors that directly inhibit HIV-1 replication. The exact mechanisms underlying the anti-HIV activity of IFNα are not completely understood and are very complex because IFNα is comprised of 12 distinct subtypes that possess diverse biological properties. HIV infection of a target cell can be sensed by multiple pattern recognition receptors, which leads to the production of type I IFNs, but if certain sensing pathways are associated with specific IFNα subtype induction is unknown. We established the Lamina Propria Aggregate Culture (LPAC) model to characterize the induction of specific IFNα subtypes by HIV in mucosal lymphocytes. To precisely quantify IFNα subtype proteins in complex biological samples we will set up a unique mass spectrometry assay. Beside the induction of IFNα subtypes we also want to characterize their individual signaling pathways and we will define the protein regions or single amino acids that are critical for the strong anti-HIV effects of certain IFNα subtypes. This project should provide new insights into how the induction of different type I IFNs and the activation of downstream signaling pathways may impact mucosal HIV-1 infection and pathogenesis. These results shall help to develop strategies that aim to use specific IFNα subtypes or IFNα hybrids/mutants for immunotherapy against HIV infection.

肠道相关淋巴组织（GALT）对于HIV-1感染的最初建立和传播至关重要。目前认为，I型干扰素（IFN），诱导宿主先天免疫应答过程中的各种模式识别受体，在抵消最初的病毒传播中发挥了关键作用。I型IFN在早期HIV-1感染中被诱导，并且大量产生I型IFN的浆细胞样树突状细胞被迅速募集到感染的粘膜部位。I型IFN可能通过增加直接抑制HIV-1复制的限制因子的表达和活性来抑制HIV-1。IFNα抗HIV活性的确切机制尚未完全了解，并且非常复杂，因为IFNα由12种具有不同生物学特性的不同亚型组成。HIV对靶细胞的感染可以被多种模式识别受体感知，从而导致I型IFN的产生，但某些感知途径是否与特定的IFNα亚型诱导相关尚不清楚。我们建立了粘膜固有层聚集体培养（LPAC）模型，以表征HIV在粘膜淋巴细胞中诱导特异性IFNα亚型。为了精确定量复杂生物样品中的IFNα亚型蛋白，我们将建立一种独特的质谱分析方法。除了IFNα亚型的诱导外，我们还希望表征其个体信号传导途径，并将定义对某些IFNα亚型的强抗HIV作用至关重要的蛋白质区域或单个氨基酸。该项目将为不同I型IFN的诱导和下游信号通路的激活如何影响粘膜HIV-1感染和发病机制提供新的见解。这些结果将有助于开发旨在使用特定IFNα亚型或IFNα杂合体/突变体用于抗HIV感染的免疫治疗的策略。