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.

The previously described activation of RIG-I-mediated immune responses in HCV-infected cells indicates that at least a portion of the viral RNA is present in regions of the cytoplasm containing RIG-I (reviewed in [77] ). We envisage several scenarios that might allow RIG-I to interact with viral RNA despite their largely segregated localization patterns in infected cells. First, previous analysis of the HCV-induced immune response showed that RIG-I-mediated signalling is activated at early time points after infection [29] . Thus, RIG-I activation in HCVinfected cells could occur through an interaction with viral RNA prior to the establishment of a fully compartmentalized MW. Alternatively, viral ssRNA, which can associate with and activate RIG-I in the absence of dsRNA, could passively or actively exit the MW to the surrounding cytosol, potentially for the purpose of translation, where it could be recognized by RIG-I and initiate immune activation [78] . In both models, immune evasion through concealment of PAMPs would not be sufficient to block all immune activation, which is likely why the virus employs a number of other immune evasion strategies that have been previously described (reviewed in [79, 80] ). Interestingly, these models predict that RLRs could only access viral positive-strand RNA, while double-stranded viral RNA is protected in the MW. This may explain why it has been difficult to observe MDA5-mediated immune activation, as MDA5 does not recognize ssRNA [29, 78] .