Role of Shiftless in HIV infection: Antiviral mechanism and contribution to innate immune responses

干扰素（IFN）系统构成了抵抗病毒感染的第一道防线。干扰素系统的传感器识别入侵病毒并诱导干扰素的表达。随后，IFN与未感染细胞的结合诱导编码具有抗病毒活性的蛋白质的几个基因的表达。结果，细胞转变成抗病毒状态。最近的一项研究表明，IFN诱导Shiftless（SFL）蛋白的表达，该蛋白通过抑制病毒多聚蛋白Gag-Pol表达所需的-1程序性核糖体移码事件（-1PRF）来抑制人类免疫缺陷病毒（HIV）感染。然而，目前尚不清楚SFL如何抑制-1PRF，以及在何种程度上抑制IFN阻断HIV感染。在这个项目中，我们将阐明哪些病毒靶细胞表达SFL，并阐明SFL对IFN介导的HIV感染抑制的贡献。我们将采用体外翻译系统和诱变分析来揭示SFL如何干扰-1PRF。最后，确定SFL、病毒RNA和核糖体的复合物的结构。总的来说，SFL在HIV感染中的作用将被分析，总体目标是了解先天免疫如何抑制逆转录病毒感染。

The interferon (IFN) system constitutes the first line of defense against viral infection. Sensors of the IFN system recognize invading viruses and induce the expression of IFN. Subsequently, the binding of IFN to uninfected cells induces the expression of several genes encoding for proteins with antiviral activity. As a consequence, the cell transits into an antiviral state. A recent study shows that IFN induces the expression of the Shiftless (SFL) protein, which inhibits human immunodeficiency virus (HIV) infection by suppressing a –1 programmed ribosomal frameshifting event (–1PRF) required for expression of the essential viral polyprotein Gag-Pol. However, it is currently unclear how SFL inhibits –1PRF and to what extend inhibition contributes to blockade of HIV infection by IFN. In this project, we will clarify which viral target cells express SFL and elucidate the contribution of SFL to IFN-mediated inhibition of HIV infection. We will employ in vitro translation systems and mutagenic analysis to reveal how SFL interferes with –1PRF. Finally, the structure of the complex of SFL, viral RNA und ribosome will be determined. Collectively, the role of SFL in HIV infection will be analyzed with the overall goal of understanding how innate immunity can inhibit retroviral infection.