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.

One proposed function for the MW is to conceal viral replication intermediates from cytoplasmic pattern recognition receptors (PRRs) and to limit host cell immune activation [9, 24] . Recognition of viral pathogen-associated molecular patterns (PAMPs), including doublestranded RNA (dsRNA), single-stranded RNA (ssRNA), and polyuridine signatures, is an important mechanism for immune activation in host cells. In virus-infected cells, PAMP recognition is accomplished primarily by Toll-like receptor 3 (TLR3) in endosomes or at the plasma membrane, and by RIG-I-like receptors (RLRs) in the cytosol. RLR's include RIG-I and MDA5, which are cytoplasmic proteins that each contains two caspase-recruitment domains (CARDs) and a DExD/H-box helicase domain [25] . Both RIG-I and MDA5 interact with viral RNA molecules, with RIG-I preferentially recognizing 5'-phosphorylated blunt ends of viral genomic dsRNA and MDA5 binding long stretches of dsRNA [26] [27] [28] . Importantly, RIG-I also recognizes HCV ssRNA, binding to both the 5'ppp and the poly-U/UC region in the 3' NTR [29] . Ligand recognition by either RIG-I or MDA5 results in activation of MAVS, nuclear translocation of IRF-3 and NF-κB, and transcriptional activation of early immune response genes [30] [31] [32] [33] .