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

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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.