Eukaryotic initiation factor 5B: A new player for the anti-hepatitis C virus effect of ribavirin?

The addition of the broad-spectrum antiviral agent ribavirin (RBV), a synthetic guanosine analog, to interferon-alpha (IFN alpha) monotherapy has been a major breakthrough in the treatment of patients with hepatitis C virus (HCV), as it greatly improved treatment response rates. Although several mechanisms of action have been proposed for RBV's antiviral activity, each with some experimental evidence, the precise mechanism by which it acts synergistically with IFN alpha has remained elusive. A cornerstone of the antiviral IFN alpha response is phosphorylation of the alpha subunit of eukaryotic initiation factor (eIF)2. This limits the availability of eIF2 GTP.Met-tRNA(i)(Met) ternary complexes, reduces formation of the 435 preinitiation complexes, ultimately blocking viral (and most cellular) mRNA translation. However recent studies indicated that translation driven by the HCV internal ribosome entry site (IRES) is insensitive to eIF2 alpha phosphorylation. Particularly, in addition to the general eIF2-dependent pathway of translation, the HCV IRES makes use of a bacterial-like, eIF2-independent pathway requiring as initiation factors only eIF5B (an analog of bacterial IF2) and eIF3. Together, these observations support a model in which cellular stresses that induce eIF2 alpha phosphorylation (e.g. treatment with IFN alpha cause HCV IRES-directed translation to switch from an eIF2-dependent mode to an eIF5B-dependent mode, defining a tactic used by HCV to evade the INF alpha response. Eukaryotic eIF5B is a ribosome-dependent GTPase that is responsible for 80S complex formation in translation initiation but shows much lower affinities for GTP than to other GTPases, thus suggesting that it may mis-incorporate the RBV triphosphate (RTP) in place of GTP even at the RBV concentrations achieved in clinical use. Consequently, we theorize that RTP bound to eIF5B lowering its affinity for ribosome, blocks the 80S complex formation on HCV IRES inhibiting the eIF5B-dependent translation used by HCV to elude IFN alpha response. n conclusion, our hypothesis provides a mechanistic explanation for the phenomenon of RBV enhancement in INF alpha-based therapy. (C) 2012 Elsevier Ltd. All rights reserved.