The Hepatitis C Virus-Induced Membranous Web and Associated Nuclear Transport Machinery Limit Access of Pattern Recognition Receptors to Viral Replication Sites

Neufeldt, Christopher J.; Joyce, Michael A.; Van Buuren, Nicholas; Levin, Aviad; Kirkegaard, Karla; Gale Jr., Michael; Tyrrell, D. Lorne J.; Wozniak, Richard W.

Much like other membrane-bound organelles, the membrane structures induced by positivestrand RNA viruses serve to both concentrate proteins within a specific area, thereby increasing efficiency of certain processes, and to spatially separate competitive reactions. A proposed function of sequestering viral replication complexes away from the surrounding cytosol is the concealment of viral PAMPs from RLRs, a process that is predicted to attenuate host cell innate immune activation. On the basis of previous data and that presented here, we propose that structural features of the MW, including components of the nuclear transport machinery, establish a selective permeability barrier between the surrounding cytosol and viral replication and assembly centers within the MW [8, 23, 37, 38, 57] . We show here that this barrier facilitates viral infection by inhibiting the access of RLRs to regions within the MW. These conclusions are supported by our findings that the addition of NLS sequences to either RIG-I or MDA5, which allows these proteins to interface with the nuclear transport machinery, overcome the barrier that restricts their access to compartments within the MW. A consequence of NLS-mediated movement of RLRs into the MW is increased immune activation and the inhibition of viral replication.