To gain further insight into the different stages of the viral lifecycle targeted by our SKI-1/S1P inhibitor, we used an activesite-directed small-molecule inhibitor of SKI-1/S1P, PF-429242. This pharmacologic inhibitor of SKI-1/S1P has recently been characterized for its effectiveness in blocking cleavage of SREBP-2, for blocking expression of SREBP-activated genes, and also for inhibiting arenavirus glycoprotein processing [64, 84] . In contrast to our recombinant adenovirus-expressed serpins, PF-429242 can be added extracellularly to rapidly inhibit SKI-1/S1P. This allows us to study the biological impact of blocking SKI-1/S1Pdependent pathways during both early and late stages of HCV infection.