Regulation of the induction of IFNα subtypes during HIV infection

肠道相关淋巴组织(GALT)对HIV-1感染的初始建立和传播至关重要。目前认为，I型干扰素(IFN)在宿主先天免疫反应中由多种模式识别受体诱导，在对抗初始病毒传播中发挥关键作用。I型IFN在HIV-1感染早期被诱导，大量产生I型IFN的浆细胞样树突状细胞迅速被招募到粘膜感染部位。I型干扰素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。由于干扰素α由12个不同的亚型组成，具有不同的生物学特性，因此干扰素α的确切抗艾滋病毒作用机制尚不完全清楚，而且非常复杂。HIV对靶细胞的感染可以被多个模式识别受体感知，从而导致I型α的产生，但特定的感知途径是否与特定的干扰素IFN亚型诱导有关尚不清楚。我们建立了普罗普里亚层聚集培养模型，以研究人类免疫缺陷病毒对粘膜淋巴细胞中特异性干扰素α亚型的诱导。为了准确定量复杂生物样品中的干扰素α亚型蛋白，我们将建立一种独特的质谱分析方法。除了干扰素α亚型的诱导作用外，我们还希望研究它们各自的信号通路，并确定某些干扰素α亚型发挥强大抗艾滋病作用所必需的蛋白质区域或单一氨基酸。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。这些结果将有助于制定旨在使用特定干扰素α亚型或干扰素α杂交体/突变体进行免疫治疗以对抗艾滋病毒感染的策略。

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.