The interferon (IFN) system is the first line of defense against invading viruses. Sensors of the IFN system recognize viruses and induce the expression of IFN. Binding of IFN to uninfected cells eventually triggers the expression of numerous genes, the products of which can inhibit viruses. Cells are said to enter an antiviral state. A new paper shows that IFN triggers the formation of the protein Shiftless (SFL) and that SFL inhibits human immunodeficiency virus (HIV) infection by blocking a programmed ribosomal reading frame shift (PRL), thereby suppressing the expression of the essential polyprotein Gag-Pol. However, how SFL inhibits the reading frame shift and to what extent SFL contributes to IFN-mediated inhibition of HIV is unclear. This project will clarify in which HIV target cells SFL is expressed and the extent to which inhibition of SFL expression reduces HIV inhibition by IFN. In addition, in vitro translation systems and mutagenesis will be used to determine how SFL interferes with PRL. Finally, the structure of SFL in complex with viral RNA and ribosome will be elucidated. In summary, the role of SFL in HIV infection will be investigated with the goal of better understanding how the innate immune response can inhibit the virus.