TWiV 121: Huskies go viral

viral huskiesHosts: Vincent Racaniello, Michael Katze, Michael Gale, Deborah Fuller, and Shawn Iadonato

Episode #121 of the podcast This Week in Virology is a conversation about careers in virology, systems biology, innate immunity, and antiviral research recorded at the University of Washington in Seattle.

Click the arrow above to play, or right-click to download TWiV #121 (65 MB .mp3, 90 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 the Microbeworld app.

Links for this episode:


Weekly Science Picks

Michael K – Pasteur Museum
Deborah – Undaunted Courage by Stephen Ambros
Michael G – The Eighth Day of Creation by Horace Freeland Judson
Vincent –
The Emperor of All Maladies by Siddhartha Mukherjee

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.

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.

A new target for hepatitis C virus

When infection with hepatitis C virus goes from acute to chronic, severe liver disease may occur which requires organ transplantation. Nearly 200 million people are chronically infected with HCV, necessitating approaches to preventing and treating infections. No HCV vaccine is available, and current antiviral therapy consists of administration of interferon plus ribavirin, a combination that is effective about half the time and is associated with undesirable side effects. New antiviral compounds that target a viral protease and RNA polymerase are currently in clinical trials may eventually reach the market. But our experience with HIV-1 has shown that combinations of three drugs are the most effective for derailing the emergences of drug resistant viruses. The third target for HCV could be NS5A, a viral protein without a known function.

To identify new inhibitors of HCV, a chemical library of one million compounds was screened for the ability to inhibit viral replication in cell culture. The active compound were then subjected to a second screen to eliminate inhibitors of known viral enzymes: the viral protease, RNA polymerase, and helicase. One of the remaining inhibitors was further refined chemically until a very potent derivative was obtained. This molecule, called BMS-790052, has a 50% inhibitory concentration in the picomolar range, and inhibits all the viral genotypes tested. It is the most powerful inhibitor of HCV discovered.

The compound was tested for safety and bioavailability in various animal species. After oral administration, the compound was found in plasma and liver, despite a molecular mass of over 700 daltons. Six different levels of the compound were tested in HCV infected individuals. No adverse effects were reported, and the highest amount administered reduced viral levels in the blood 2,000 fold after one day. These results are promising, but larger trials will now be needed to further confirm the safety and efficacy of the drug.

What is the target of BMS-790052? Two lines of evidence suggest that the compound inhibits the viral protein NS5A. The drug appears to bind NS5A, and viruses resistant to the drug have amino acid changes in this protein. Although NS5A is known to be required for viral replication, its precise function is not known. Because NS5A does not have an easily assayable enzymatic function, it has not previously been a target of drug discovery. The identification of a compound that inhibits NS5A function is an important step forward in HCV drug development. The general approach used to discover BMS-790052 should be useful in identifying inhibitors of other viral proteins that do not have well defined and measurable activities.

I discussed this paper on Futures in Biotech episode #60. If you would like to listen only to the conversation about BMS-790052, download this mp3 file, or listen to the discussion below.

[audio:http://www.virology.ws/fib60.mp3 | titles=FIB 60]

Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun JH, O’Boyle DR 2nd, Lemm JA, Wang C, Knipe JO, Chien C, Colonno RJ, Grasela DM, Meanwell NA, & Hamann LG (2010). Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature, 465 (7294), 96-100 PMID: 20410884

TWiV 85: Hepatitis C virus with Professor Michael Gale

Hosts: Vincent Racaniello and Michael Gale

On episode 85 of the podcast This Week in Virology, Vincent and Michael Gale discuss the origin, pathogenesis, prevention, of hepatitis C virus, and how it evades innate immune responses.

This episode is sponsored by Data Robotics Inc. Use the promotion code TWIVPOD to receive $75-$500 off a Drobo.

Click the arrow above to play, or right-click to download TWiV #85 (40 MB .mp3, 56 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:

  • The Gale Laboratory at the University of Washington
  • Incredible view from the Gale laboratory (jpg)
  • Evasion and disruption of innate immune signalling by hepatitis C and West Nile viruses (review)
  • New potent HCV inhibitor
  • HCV virion and genome structures at ViralZone

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.

Futures in Biotech 60: Do you come to this cave often?

I joined Marc Pelletier on futures-in-biotechepisode 60 of Futures in Biotech for a conversation with Dave Brodbeck, George Farr, and Andre Nantel. We talked about primate face recognition, discovery of a new antiviral compound to treat hepatitis C virus infection, changing the length of a codon from three to four bases, and the sequence of the neanderthal genome.

[audio:http://www.podtrac.com/pts/redirect.mp3/twit.cachefly.net/fib0060.mp3 | titles=FiB 60]

Download FiB #60 (44 MB .mp3, 91 minutes)

Video courtesy of Team ODTV

 

Download video (179 MB .mp4)

Mouse model for hepatitis C virus infection?

pvrtgNo, not yet. But the recent identification of human occludin as a cell protein required for entry of hepatitis C virus into mouse cells is a huge step in the right direction.

Small animal models for virus infection are of great value for studying viral pathogenesis, testing new vaccines, and developing antiviral drugs. However, mice are often not susceptible or permissive for infection by many important viruses. For example, mice and mouse cells are permissive for poliovirus replication, but are not susceptible to infection with the virus. Mice can be made susceptible to poliovirus infection by transgenic expression of the human poliovirus receptor. In a similar way, a transgenic mouse model for measles virus infection has been produced. But it has been far more difficult to create transgenic mice susceptible to other important viruses, including HIV-1 and hepatitis C virus (HCV).

Mouse cells are permissive for HCV replication (the viral RNA can replicate when transfected into cells), but they are not susceptible: for example, they cannot be infected by lentiviral particles bearing HCV glycoproteins.  Three cellular proteins required for HCV entry into cells were previously identified: CD81, scavenger receptor class B type I or SCARB1, and claudin-1. Most recently a fourth cellular protein, occludin, was found to be essential for HCV entry into cells. HCV can enter mouse cells that synthesize human occludin and CD81; apparently the murine versions of SCARB1 and claudin-1 can promote HCV entry. The human versions of these four proteins was sufficient to confer permissivity to HCV entry in a variety of human, murine, or hamster cell lines.

Because the major block to HCV entry in murine cells can be overcome by synthesis of human CD81 and occludin, will it now be possible to produce transgenic mice susceptible to HCV? Perhaps not yet: there are other blocks to HCV replication in murine cells. For example, viral RNA replication in mouse cells is not efficient, nor has assembly of infectious virions been demonstrated. But these problems can now be readily addressed, and I would not be surprised to find that CD81/occludin transgenic mice already exist and are being tested for susceptibility to HCV in at least one laboratory.

Ploss, A., Evans, M., Gaysinskaya, V., Panis, M., You, H., de Jong, Y., & Rice, C. (2009). Human occludin is a hepatitis C virus entry factor required for infection of mouse cells Nature, 457 (7231), 882-886 DOI: 10.1038/nature07684