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.