Hepatitis C virus RNA and activation of innate immunity

Virus-host interactions are characterized by a remarkable sequence of "one-upmanship" responses that alternately tip the advantage between the pathogen and the infected cell. New evidence suggests that viral RNA molecules are recognized as foreign invaders by cytoplasmic proteins that are RNA helicases and innate immune signaling molecules. These helicases (called RIG-I, MDA5, and LGP2) act independently of the toll-like receptor (TLR) pathways to stimulate interferon expression and the establishment of an anti-viral state.

We have found that viral RNAs are not equal in terms of their abilities to activate innate immune signaling. Specifically, our data indicate that the 5' and 3' untranslated regions of dengue virus and West Nile virus RNAs are very weak activators in comparison with the 3' untranslated region of hepatitis C virus (Sumpter, 2005). The goal of our work is to identify RNA sequence and structural features that activate innate immune signaling through the cytoplasmic RNA helicases RIG-I and MDA-5.

Graduate student Dina Uzri has identified a small region in the 3' untranslated region of the hepatitis C virus RNA that is responsible for potent activation of innate immune signaling. As a clue toward understanding the signaling mechanisms, chemical modifications to the RNA block interferon expression, but without effect on the RNA-RIGI binding interaction. The data further suggest that the level of innate immune signaling observed with a given RNA is directly related to the nucleotide sequence of the stimulating RNA.

Current work is directed at understanding how the activating sequence contributes to both replication and innate immune signaling in the context of HCV replicon RNAs.

Sumpter, R., Jr., Y. M. Loo, E. Foy, K. Li, M. Yoneyama, T. Fujita, S. M. Lemon, and M. Gale, Jr. 2005. Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J Virol 79:2689-99.