HCV: Activation of Innate Immunity by Cytoplasmic Viral RNA

How does a cell distinguish its own (self) RNAs from those of invading viral pathogens (non-self?).

Hepatitis C virus (HCV) is a member of the family Flaviviridae. Like other viruses studied in the Gehrke laboratory, the genome is a positive strand RNA that does not have a poly(A) tail at the 3' end. Recent work from a number of laboratories has demonstrated that viral RNAs can act as Pathogen-Associated Molecular Patterns (PAMPs) that are recognized by Pattern Recognition Receptors (PRRs), leading to activation of innate immune signaling.

To understand more about the cellular innate immune response to self versus non-self RNAs, we compared the abilities of the 5' and 3' untranslated regions (UTR) of flavivirus and HCV RNAs to cytoplasmic innate immune signaling through cytoplasmic RIG-I, an RNA helicase that is independent of Toll-like receptors (TLRs).

Dina Uzri, a graduate student in the Virology Program at Harvard Medical School, has discovered that the HCV 3' UTR elicits significantly more signaling activity than dengue virus, West Nile virus, and Yellow Fever virus RNAs. Surprisingly, the activation sequence is a polyU/UC domain, which has very little potential for forming secondary structure in contrast to most reports, which state that double-stranded RNA is that signaling determinant. Modifying the polyU/UC RNA with 2'-fluoro uridine blocks the innate immune activation but not not impair the RNA binding to the RIG-I helicase.

Current work is directed at testing the hypothesis that levels of RIG-I signaling activation are defined by specific nucleotide sequences in viral RNAs.