Finally, we wanted to investigate the impact of blocking S1Pmediated GP processing on virus progeny of authentic LASV. Therefore, we assessed the inhibitory potential of the most potent variant, a 1 -AT RRIL, on the multiplication of LASV (strain Josiah). For this purpose a 1 -AT RRIL cells and, as controls, CHO-K1-Tet-On and SRD-12B cells were infected with LASV at an MOI of 0.1. To induce a 1 -AT expression, a 1 -AT RRIL cells and, as a control for off-target effects, CHO-K1 Tet-On cells were cultivated in the presence of doxycycline. To determine virus titers, infectious virions released into the cell culture supernatant were analyzed by defining the 50% tissue culture infectious dose (TCID 50 ) at various times post-infection, as indicated. In noninduced a 1 -AT RRIL cells, LASV revealed a growth kinetic similar to that observed in CHO-K1 Tet-On control cultures, while expression of a 1 -AT RRIL resulted in an average 2 log10 reduction in viral titer (Fig. 6) . The difference between infectious LASV titers in the supernatant of a 1 -AT RRIL expressing cells and SRD-12B cells correlated with the limited virus spread observed in a 1 -AT RRIL expressing cells compared to single cell infections in S1P null cells (Fig. 5) . Taken together, this result highlights the inhibitory activity of modified a 1 -antitrypsins against LASV and demonstrates that inhibition of endogenous S1P is a potent strategy to reduce the production of infectious LASV progeny.