The outcome of severe illness increased significantly with the level of viremia in Lassa fever patients [70] . Therefore, the extent of multicycle replication of LASV and thus, the load of infectious particles in its host organism have an important impact for the progress of disease. Our studies revealed that a 1 -AT variants RRIL and RRLL have a potency sufficient to sustain their inhibitory capacity during multicycle replication, which resulted in a significant reduction of virus infectivity. Inhibition of viral replication correlated with the ability of the a 1 -AT variants RRIL and RRLL to efficiently inhibit the processing of the LASV glycoprotein precursor. Although our data demonstrated that inhibition of glycoprotein cleavage by a 1 -AT RRIL reduced incorporation of the subunits GP-1 and GP-2 into virions to below detectable levels, the viral titer from a 1 -AT RRIL expressing cells was found to be greater than that obtained from S1P null cells. Based on this observation, we consider that even the most potent a 1 -AT variant RRIL failed to entirely inhibit S1P activity. However, given that S1P has important biological functions in the regulation of various cellular processes, a complete inhibition of the catalytic activity of S1P is not desirable. For a 1 -AT variants RRVL and RRYL, we observed similar inhibition values by immunoblot quantification analysis as described for CCHFV GP cleavage [42] . Though, their inhibitory activity on LASV GP-C cleavage was not sufficient to efficiently reduce virus replication of VSVDG/LASVGP. These results should be taken into consideration for experimental setups in future studies that address the impact of S1P inhibition in arenavirus replication.