Sunday, October 28, 2007

Journal Club: A commonly used treatment for HCV, Interferon Beta, may largely act through microRNAs

While on vacation, an interesting study on the effect of interferon beta on microRNA levels was published in the journal Nature (Pedersen et al.: Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature doi:10.1038/nature06205).

In this study, Pedersen and colleagues were initially interested in whether interferons had the potential to modulate cellular microRNA levels. Not very surprisingly, this potent class of cytokines up- and downregulated a number of microRNAs. Strikingly, however, eight of the interferon beta-induced microRNAs had microRNA seed complementarities with an HCV genome. Moreover, miR-122, a microRNA that has now been shown by a number of laboratories now to facilitate HCV replication, was downregulated by interferon beta.

The link between HCV and interferon-regulated microRNAs is intriguing, since interferon beta is at the center of current HCV treatment regimens. In order to test whether the antiviral activity of interferon beta on HCV replication was indeed mediated by microRNA regulation, the authors asked whether interferon beta could still inhibit HCV replication in the presence of mimics of the upregulated and HCV matching microRNAs and an inhibitor of miR-122. In agreement with the notion that interferon-regulated microRNAs mediate a large part of interferon beta inhibition of HCV, such a mixture of small RNAs alleviated interferon beta inhibition of HCV replication from 90% to around 50% of untreated control in a tissue culture system.

HCV has a long-standing tradition in the RNAi Therapeutics field. As such, a number of drug candidates are expected to enter the clinic in the near future that directly target the HCV genome by RNAi. In addition, since HCV replication is supported by miR-122, it has become the focus of the first wave of microRNA-targeting therapeutic programs. Due to the ability of viruses to escape drug inhibition through mutation, a combination of these approaches appears promising. As much as no other current HCV antiviral alone can reliably get rid of HCV altogether, I do not expect any RNAi-related stand-alone therapy for HCV to be successful. However, when combined with potent agents such as Vertex Pharmaceutical’s late-stage protease inhibitor VX-950, RNAi may be able to further knock down HCV sufficiently so that it can be entirely cleared by the body. Moreover, many patients do not complete interferon therapy due to its severe side-effect profile, and alternatives are desirable. The strategy proposed in the paper may therefore lead to a treatment that works through the same antiviral pathway as interferon beta, but without the side-effects.

Lastly, I would like to briefly comment on the evolutionary aspects of the studies. It is very unlikely, given the rapid evolution of viruses alone, that the sequence of the implicated microRNAs was shaped due to selection based on HCV inhibition. Accordingly, the authors find that the sites complementary to the microRNA seeds are not all conserved in the different HCV genotypes (note: whether this is related to the varying efficacy of interferon beta on different genotypes in the clinic was not discussed). It is only through comparing the modulated microRNAs with a lot of viruses that they found the link with HCV. It is therefore fortuitous that interferon-modulated microRNAs should have anti-HCV activities. Of note, this is similar to a paper published 2 years ago in the journal Science (Lecellier et al.: A cellular microRNA mediates antiviral defense in human cells. Science 308: 557) which showed for the first time that a cellular microRNA may restrict the replication of a mammalian virus through good fortune.

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By Dirk Haussecker. All rights reserved.

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