TWiV 166: Breaking and entering

npc1 ebolaHosts: Vincent Racaniello, Dickson DespommierRich Condit, and Alan Dove

Vincent, Dickson, Rich, and Alan review cell proteins essential for entry of hepatitis C, Ebola, and measles viruses.

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Click the arrow above to play, or right-click to download TWiV 166 (59 MB .mp3,  98 minutes).

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Links for this episode:

Weekly Science Picks

Dickson – What are you swimming with?
Rich –
Twelve monkeys
AlanKindle Touch
Vincent – Microbe news (thanks to Dave Winer)

Listener Pick of the Week

EricThe Nature of Things with David Suzuki
LanceTrials and Errors (Wired)

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TWiV 150: Contaminated

pXMRVHosts: Vincent RacanielloRich Condit, and Dickson Despommier

Vincent, Dickson, and Rich meant to do an all-email episode, but first they review results of the Blood XMRV Scientific Research Working Group, and partial retraction of the paper associating XMRV with chronic fatigue syndrome.

With this episode TWiV is three years old.

Click the arrow above to play, or right-click to download TWiV 150 (56 MB .mp3, 93 minutes).

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Links for this episode:

Weekly Science Picks

Dickson – The Tree of Life
Vincent –
When do you fact-check article content with sources? (take as directed)
Rich –
io9

Listener Pick of the Week

LuisNIH videocasting and podcasting

Send your virology questions and comments (email or mp3 file) to twiv@microbe.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

TWiV 141: Mickey gets HCV

hcv miceHosts: Vincent Racaniello, Rich ConditDickson DespommierAlan Dove, and Matt Evans

Matt Evans joins Vincent, Rich, Dickson, and Alan to deconstruct a mouse model for hepatitis C virus infection.

Click the arrow above to play, or right-click to download TWiV #141 (117 MB .mp3, 97 minutes).

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Links for this episode:

Weekly Science Picks

Matt – Benezra letter to NIH (pdf); (NIH response and Nature commentary)
Dickson –
The Big Thirst by Charles Fishman
Alan –
Earth’s First Steps by Jerry MacDonald
Rich – Final space shuttle launch and NIAID paylines
Vincent – Hertog Global Strategy Initiative

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TWiV 137: Look what the dog dragged in

dog_humanHosts: Vincent Racaniello, Alan Dove, Rich Condit, Dickson Despommier, Amit Kapoor, and Ian Lipkin

The TWiV team speaks with Amit Kapoor and Ian Lipkin about how they discovered canine hepacivirus, and its implications for the origin and evolution of hepatitis C virus.

Click the arrow above to play, or right-click to download TWiV #137 (69 MB .mp3, 96 minutes).

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Links for this episode:

Weekly Science Picks

Alan – What do marine mammals eat? (YouTube)
Rich
NIH rocket boys
Dickson – Cytomegalovirus needs an antiviral protein (Science)
Vincent – All pdfs free at National Academy of Science Press

Listener Pick of the Week

Adriana and Ye Jung  – The man who was cured of AIDS (article one and two)

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Canine hepacivirus, a relative of hepatitis C virus

yellow labradorContemporary human viruses most likely originated by cross-species transmission from non-human animals. Examples include HIV-1, which crossed from chimpanzees to humans, and SARS coronavirus, which originated in bats. Since the 1989 discovery of hepatitis C virus (classified as a hepacivirus in the family Flaviviridae) the origin of the virus been obscure. During the characterization of respiratory infections of domestic dogs, a virus was discovered that is the most genetically similar animal virus homolog of HCV.

HCV is a substantial human pathogen: 200 million people worldwide are chronically infected and are at risk for the development of hepatocellular carcinoma. The source of HCV is unknown because there are no closely related animal virus homologs, but the hunt for related viruses has focused mainly on nonhuman primates. The identification of a related virus was fortuitous, and came about during a study of respiratory viruses that infect dogs. Nasal swabs were obtained from dogs with respiratory illness in shelters in Texas, Utah, and Pennsylvania. Sequence analysis of viral nucleic acids revealed the presence of a virus related to HCV, which was named canine hepacivirus (CHV). The virus was found in respiratory samples from 6 of 9 and 3 of 5 dogs in two separate outbreaks of respiratory disease, but not in 60 healthy pet dogs.

CHV was present in liver, but not lung, of 5 dogs that had died from unexplained gastrointestinal illness. The amount of CHV RNA in respiratory samples was substantially higher than in liver. Viral RNA was detected in the cytoplasm of hepatocytes in canine liver, but whether CHV is hepatotropic (replicates in liver cells) in dogs is not known. In humans, the amount of HCV in respiratory samples is typically very low. CHV may therefore infect different cells and tissues in dogs than does HCV in humans.

Bioinformatic analysis of CHV revealed that it is the genetically more related to HCV than any other known virus. HCV and CHV probably shared a common ancestor that circulated between 500 and 1,000 years ago – many years after dogs were domesticated. It is possible that hepaciviruses are mainly dog viruses, and that HCV arose by transmission of the virus from a dog to a human. An alternative scenario that cannot be excluded is that hepaciviruses infect many animal species. Screening of other animals for the presence of hepaciviruses must be done to determine which hypothesis is correct.

It was not possible to infect canine cultured cells with CHV, using clinical specimens from dogs.  The reason for this failure is not known, but could mean that the cells used are not susceptible and/or permissive for viral replication. Furthermore, a full-length DNA copy of the viral genome, which could be used to produce infectious viral RNA, was not reported. Propagation of the virus in cell cultures will be essential for enabling research on CHV replication and pathogenesis.

The discovery of CHV is exciting because the virus provides clues about the origins of HCV and will likely stimulate a search for related viruses in other animals. It is possible that CHV infection of dogs might be a model for understanding the pathogenesis of HCV, which currently is only possible in chimpanzees. A convenient animal model would be valuable for devising new ways to prevent and treat HCV infections.

A. Kapoor, P. Simmonds, G. Gerold, N. Qaisar, K. Jain, J.A. Henriquez, C. Firth, D.L. Hirschberg, C. Rice, S. Shields, & W.I. Lipkin. (2011). Characterization of a canine homolog of hepatitis C virus Proc. Natl. Acad. Sci. USA

TWiV 130: Rhino tracking, wrestling pox, and HCV in the crosshairs

organ culture hrv cHosts: Vincent Racaniello, Alan Dove, and Rich Condit

Vincent, Alan, and Rich discuss growth in culture of newly identified rhinovirus C, vaccinia transmission among wrestlers and martial artists, and results of phase III clinical trial of boceprevir, a new inhibitor of hepatitis C virus replication.

Click the arrow above to play, or right-click to download TWiV #130 (45 MB .mp3, 93 minutes).

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Links for this episode:

Weekly Science Picks

Rich – Rock-paper-scissors vs computer (thanks, Megan!)
Alan –
WebCite
Vincent – Edward Jenner Museum (EID)

Listener Pick of the Week

Derek Tolly  – A Paralyzing Fear: The Story of Polio in America (IMDb)

Send your virology questions and comments (email or mp3 file) to twiv@microbe.tv, or call them in to 908-312-0760. 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)

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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.

TWiV 86: Dark matter with Dr. Eric Delwart

Hosts: Vincent Racaniello, Rich Condit, and Eric Delwart

In episode #86 of the podcast This Week in Virology, Vincent and Rich travel to the Blood Systems Research Institute in San Francisco to speak with Eric Delwart about his work on virus discovery.

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

To enter a drawing to receive 50% off the manufacturers suggested retail price of a Drobo S or FS at drobostore.com, fill out the questionnaire here.

Click the arrow above to play, or right-click to download TWiV #86 (59 MB .mp3, 81 minutes)

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Links for this episode:

Weekly Science Picks

Rich – Google Crisis Response – Gulf of Mexico Oil Spill
Vincent
HHMI resources for teachers and students (thanks, Jim!)
EricVaccine by Arthur Allen

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)

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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.