TWiV 346: A double helical career

Episode #346 of the science show This Week in Virology was recorded at the 34th Annual Meeting of the American Society for Virology, where Vincent, Rich, and Kathy spoke with Joan Steitz, a tireless promoter of women in science and one of the greatest scientists of our generation.

You can find TWiV #346 at www.microbe.tv/twiv.

TWiV 324: Viruses in the miR may appear more numerous

On episode #324 of the science show This Week in Virology, Lee joins the TWiV team to discuss the value of post-doctoral training, and how a cellular microRNA assists in the replication of hepatitis C virus.

You can find TWiV #324 at www.microbe.tv/twiv.

TWiV 264: We should do an all-email show some day

On episode #264 of the science show This Week in Virology, the TWiVites read listener questions and comments about public engagement in science, vaccines, RNAi, reprogramming CD8 cells to treat cancer, rabies, and much more.

You can find TWiV #264 at www.microbe.tv/twiv.

TWiV 256: How mice say nodavirus

On episode #256 of the science show This Week in Virology, Vincent, Dickson, Alan, Rich, and Kathy review two papers that present evidence for RNA interference as an antiviral immunity mechanism in mammals.

You can find TWiV #256 at www.microbe.tv/twiv.

TWiV 255: Longhorns go viral

On episode #255 of the science show This Week in Virology, Vincent and Rich visit the University of Texas at Austin and meet up with Bob and Chris to talk about their work on influenza virus and microRNAs.

You can find TWiV #255 at www.microbe.tv/twiv.

Treating hepatitis C by blocking a cellular microRNA

HCV UTRMiravirsen is a drug that binds to and blocks the function of a cellular microRNA called miR-122 that is required for the replication of hepatitis C virus (HCV). Treatment of chimpanzees chronically infected with HCV with this drug leads to suppression of viral replication. The results of a phase 2b human clinical trial in HCV infected humans indicate that Miravirsen reduces levels of viral RNA without evidence for viral resistance. I asked virologist Stan Lemon (who appeared recently on TWiV 235) his opinion of these findings.

Are you surprised that the antiviral effect of Miravirsen is long lasting?

The Janssen study published in NEJM basically recapitulated what Lanford had observed in HCV-infected chimps treated with the compound, with a very slow onset of antiviral effect, and then a very slow rebound as well. This probably reflects the pharmacokinetics and very high stability of the locked nucleic acid compound, and the time required to sequester endogenous miR-122 – changes in serum cholesterol also move very slowly. I think this is why the antiviral effect (and cholesterol effect) are long-lasting.

Is it surprising that no resistance to Miravirsen was observed?

As for the lack of resistance, it doesn’t surprise me much. This was observed in the chimps as well. The virus is really dependent upon miR-122 for its replication, and can’t readily mutate around it – the requirement for miR-122 reflects more than just the stabilizing effect of miR-122 on the viral genome, as we showed in a recent PNAS paper (Li et al., Proc. Nat’l. Acad. Sci U.S.A., 110:1881-6, 2013) written in follow-up to our earlier demonstration of the stabilizing effect of the miRNA on the HCV genome (Shimakami et al., Proc. Nat’l. Acad. Sci U.S.A. 109: 941-6, 2012, that you reviewed in TWIV 180) – what we know and don’t know about the mechanism of action is summarized in an “opinion” piece now in press in RNA Biology.

Do you think this drug will ultimately get FDA approval?

Given issues of resistance, relapse, and poor pan-genotype coverage with direct-acting antivirals for HCV, all of this should bode well for Miravirsen. However, it has issues like almost all the new therapies under evaluation.

First, the spaghetti plots in the Janssen paper show large variation in the response of individual patients, with some having little effect when receiving Miravirsen. This is unlike studies with enzyme inhibitor antivirals, and I am not aware of any good reason for it other than potential variation in endogenous miR-122 abundance.

A second and greater issue is the cancer concern. Most hepatocellular carcinomas (except those associated with HCV, interestingly enough) demonstrate significant reductions in miR-122 abundance, and miR-122 can reverse some malignancy-associated features of transformed hepatocytes in vitro – thus, miR-122 seems to act much like a tumor suppressor in the liver.  miR-122 knockout mice develop normally but have a high incidence of hepatocellular carcinoma. I think this poses real problems for the development of Miravirsen. While one could reasonably argue that short-term exposure to the antagomir is very different than gene knockout, the patients being treated are those at the highest risk for HCC – particularly if there is advanced fibrosis or cirrhosis, which characterizes those most in need of treatment. It is also clear that HCC can manifest itself in patients AFTER therapeutic elimination of the virus. The risk is most certainly greatly reduced, but it is not zero (HCC develops very slowly, and in a multi-centric fashion), and with the evidence that the drug has relatively long-lasting effects on cholesterol (as well as the virus), I think the developers of Miravirsen may find it difficult to defend against future claims that the drug contributed to the development of HCC in some cases. There isn’t a good way to de-risk this, to show that this theoretical concern is not real, and this must be worrying the regulatory authorities – especially since there are now many alternative therapies under evaluation that don’t carry this risk, some of which are looking very good in combination with each other (e.g., advanced NS3 inhibitors, NS5A inhibitors, and nucs).

TWiV 193: Live at ASV in Madison

On episode #193 of the science show This Week in Virology, recorded at the 31st Annual Meeting of the American Society for Virology in Madison, Vincent, Rich, Carolyn, and Sara discussed genetic conflict between viral and human genes, and how the placenta protects the fetus against viral infection.

You can find TWiV #193 at www.microbe.tv/twiv.

TWiV 174: Dog runs and mooing miRs

On episode #174 of the podcast This Week in Virology, Vincent, Alan, and Rich consider whether pet dogs might transmit human noroviruses, and an RNA virus microRNA that might be involved in oncogenesis.

You can find TWiV #174 at www.microbe.tv/twiv.

TWiV 97: California virology

Hosts: Vincent Racaniello, Peter Sarnow, and Bert Semler

On episode #97 of the podcast This Week in Virology, Vincent visited Peter Sarnow and Bert Semler during a trip to California, and spoke with them about their work on internal ribosome entry, and the requirement for a cellular microRNA for hepatitis C virus replication.

Click the arrow above to play, or right-click to download TWiV #97 (66 MB .mp3, 91 minutes)

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, or by email, or listen on your mobile device with Stitcher Radio.

Links for this episode:

  • Eukaryotic mRNAs that might contain an IRES (PNAS)
  • Modulation of HCV RNA abundance by a liver-specific microRNA (Science)
  • Viral small RNAs (PLoS Pathogens)
  • Bridging IRES elements to the translation apparatus (Biochim Biophys Acta)
  • A nucleo-cytoplasmic SR protein functions in viral IRES mediated translation (EMBO J)
  • Nuclear vs cytoplasmic routes to IRES mediated translation (Trends in Microbiology)
  • Letter read on TWiV 97

Send your virology questions and comments (email or mp3 file) to twiv@microbe.tv or leave voicemail at Skype: twivpodcast. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.