virology blog

About viruses and viral disease

H5N1

TWiV 116: Cocaine, colonies, and chickens

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hive and feeding bottlesHosts: Vincent Racaniello, Alan Dove, and Rich Condit

On episode #116 of the podcast This Week in Virology, Vincent, Dickson, Alan, and Rich review an adenovirus-based vaccine strategy against drug addiction, a field trial of RNAi to prevent Israeli acute paralysis virus infection in honeybees, and suppression of avian influenza transmission in transgenic chickens.

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Click the arrow above to play, or right-click to download TWiV #116 (64 MB .mp3, 89 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:

Weekly Science Picks

Dickson – Brian Deer’s investigation of the Wakefield and MMR vaccine
Rich – Photographic periodic table of the elements
Alan – Year of the bat (site one and site two)
Vincent – EteRNA (NY Times article)

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

TWiV #78: Darwin gets weird

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Hosts: Vincent Racaniello, Alan Dove, Dickson Despommier, and Rich Condit

Vincent, Alan, Dickson, and Rich talk about treating arthritis with a tanapox virus protein, Darwinian evolution of prions in cell culture, and the connection between cold weather fronts and outbreaks of avian H5N1 influenza in Europe.

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

Win a free Drobo S! Contest rules here.

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Click the arrow above to play, or right-click to download TWiV #78 (53 MB .mp3, 73 minutes)

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, or by email.

Links for this episode:

Weekly Science Picks

Dickson Medical News Today: Infectious Diseases and Eaarth by Bill McKibben
Rich U can with Beakman and Jax by Jok Church
Alan UnderwaterTimes
Vincent The Reef Tank

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.

Influenza PB1-F2 protein and viral fitness

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influenza-rna-2The second RNA segment of the influenza virus genome encodes the PB1 protein – part of the viral RNA polymerase – and, in some strains, a second protein called PB1-F2. The latter protein is believed to be an important determinant of influenza virus virulence. The absence of a full-length PB1-F2 protein has been suggested as one possible determinant for the low pathogenicity of the 2009 influenza H1N1 pandemic strain. Analysis of the evolutionary history of PB1-F2 suggests that it does not contribute significantly to viral fitness – the ability of the virus to replicate.

PB1-F2 binds to mitochondria, leading to a release of cytochrome c and induction of apoptosis in CD8 T-cells and alveolar macrophages. The protein increases the severity of primary viral and secondary bacterial infections in mice, and is associated with the high pathogenicity of avian H5N1 and the 1918 H1N1 pandemic virus.

The PB1-F2 protein is not produced in cells infected with the 2009 H1N1 strain because there are three stop codons at nucleotide positions 12, 58, and 88.  The PB1 segment of the 2009 H1N1 strain is related to PB1 of H1N2 and H3N2 swine viruses from 1998 and human H3N2 viruses. Curiously, all the relatives of the 2009 H1N1 strain in swine and in humans encode a complete PB1-F2 protein. A truncated PB1-F2 is encoded by the genome of classical swine H1N1 viruses and human H1N1 viruses since 1947. But 96% of the avian influenza virus sequences deposited in NCBI as of 2007 encode the full length version of the protein.

Because the full-length PB1-F2 protein is not encoded in the genome of many influenza viruses, its evolutionary role and contribution to the fitness of the virus is unclear. To answer these questions, the evolution of PB1-F2 was compared with PB1 and two other open reading frames of similar size within the same RNA segment that are not translated into protein.

PB1-F2 is complete in all H1N1 human isolates before 1947, when a stop codon appeared which leads to production of a shorter version of the protein – 57 amino acids. If the complete protein conferred a functional advantage to the virus, a change in the evolutionary rates of the human H1N1 PB1-F2 proteins should have occurred in 1947. No such change is observed.

Results of sequence analysis reveal that the PB1-F2 open reading frame is as conserved, and maintained as a full-length protein, as other non-coding regions of the same RNA segment and of a randomly generated PB1 segment. These observations, and the fact that PB1-F2 is truncated in many virus isolates, suggest that the evolutionary role of PB1-F2 in animal hosts is minimal. Why the full length protein is produced by some viruses – and unfortunately leads to higher virulence – remains a puzzle.

Trifonov, V., Racaniello, V., & Rabadan, R. (2009). The Contribution of the PB1-F2 Protein to the Fitness of Influenza A Viruses and its Recent Evolution in the 2009 Influenza A (H1N1) Pandemic Virus PLoS Currents: Influenza

Influenza neuraminidase and H5N1 pathogenicity

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influenza_virion_250There are two glycoproteins embedded in the influenza viral membrane: the hemagglutinin (HA) and neuraminidase (NA). The NA, shown in yellow in the illustration, is an enzyme that removes sialic acids from the surface of the cell, so that newly formed virions can be released. The NA protein is composed of a box-like head attached to the viral membrane via a stalk. The length of the stalk may be an important determinant of the virulence of avian influenza H5N1 viruses.

Examination of the sequence of all known influenza N1 NAs reveals that the proteins can be grouped into six classes depending on the length of the stalk region. The stalk regions of some NAs are intact, while others lack from 15 to 22 amino acids. In 2000, influenza H5N1 isolates from humans were identified with a deletion of stalk amino acids 49-68. The percent of human H5N1 isolates with this deletion has steadily increased from 15.8% in 2000 to 100% in 2007. This observation led to the question: does stalk length influence H5N1 pathogenesis in animals?

The authors produced a series of H5N1 reassortant viruses with NA stalks of different lengths. Six of the 8 viral RNAs were derived from the 1933 H1N1 isolate WSN. The pathogenicity of the reassortant viruses was determined in chickens and in mice. Three of the viruses were highly pathogenic in chickens: one with the NA from a 2004 H5N1 isolate containing the deletion of amino acids 49-68, a second with the NA from WSN virus, and a third with the N1 from a 1997 H5N1 isolate. The NA stalks from the latter two viruses have deletions, but they are different from the one in the 2004 H5N1 NA. The other viruses tested were found to be of low pathogenicity in chickens. These included a virus with an N1 from an 1996 H5N1 virus with an intact stalk, as well as viruses with NAs harboring different deletions of various lengths. The findings in mice paralleled those obtained in chickens.

These results show that the NA stalk plays a critical role in virulence of H5N1 avian influenza virus in chickens and in mice. The 20 amino acid deletion from amino acids 49-68 is associated with high virulence, although similar pathogenicity was observed for viruses with different stalk deletions. These results do not answer the important question: why viruses with this particular NA deletion have become prevalent among human H5N1 influenza virus isolates. H5N1 viruses with the same stalk deletion have been isolated from aquatic birds and terrestrial poultry since 2002. It has been suggested that the stalk deletion is associated with adaptation of influenza viruses to land-based poultry, but the advantages conferred by this particular NA are unknown.

Zhou, H., Yu, Z., Hu, Y., Tu, J., Zou, W., Peng, Y., Zhu, J., Li, Y., Zhang, A., Yu, Z., Ye, Z., Chen, H., & Jin, M. (2009). The Special Neuraminidase Stalk-Motif Responsible for Increased Virulence and Pathogenesis of H5N1 Influenza A Virus PLoS ONE, 4 (7) DOI: 10.1371/journal.pone.0006277

Virulence: A positive or negative trait for evolution?

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1856663523_cffa76bfbc_mWith just 141 confirmed deaths so far, an interesting question is whether the 2009 H1N1 influenza virus could mutate into something more lethal (“How a Mild Virus Might Turn Vicious“). Of course it could – but is it beneficial for the virus?

A fundamental principle of viral evolution is that viruses must spread from host to host to maintain the viral population. A virus spreads only if an infected individual passes the virus on to more than one new host. Furthermore, infection can spread only if population density exceeds a minimal value.

Some scientists believe that increased viral virulence reduces transmissibility. When infected hosts die faster, exposure to uninfected hosts is reduced. According to Ian Lipkin:

“A really aggressive flu that quickly kills its host” – like SARS and H5N1 avian flu – “gives itself a problem”.

According to this hypothesis, virulence is selected against as the virus spreads in humans. This idea leads to statements like this one:

In the last year, dozens of H5N1 cases have been confirmed in toddlers, almost all of whom have survived – which led some experts to speculate that those are cases of a less lethal version of H5N1 that is better adapted to humans.

Why is reduced lethality equated with being better adapted to humans? And how could the virus become better adapted to humans when human to human transmission has been minimal?

There is insufficient evidence to conclude that increased viral virulence leads to reduced transmission. For example, the 1918 influenza virus strain was extremely virulent, yet spread very efficiently among humans.  SARS and H5N1 influenza aren’t good examples – SARS transmission was probably stopped by containment efforts, and H5N1 influenza virus hasn’t transmitted well among humans, if at all.

In today’s highly crowded and mobile society, even a very lethal virus can be transmitted well. Acute viral infections are preceded by an incubation period, during which virus is shed but symptoms are not yet severe enough to lead to hospitalization. And even a highly pathogenic virus will cause mild or no disease in some individuals – further increasing the chances of spreading infection.

It seems more likely that increased viral virulence could lead to better transmission. For example, a more virulent influenza virus might cause more coughing and sneezing, which would be more effective in transmitting infection. Perhaps we should focus on transmissibility, not virulence, as the property that drives viral evolution. Viruses evolve so they can be efficiently transmitted to other hosts. According to this hypothesis, any other properties that accompany transmissibility, such as virulence, are secondary effects. If this idea were true, then all viruses would evolve to be maximally infectious and avirulent. But this is not the case. Perhaps, as Peter Palese said, viral virulence has unknown benefits:

“Look, I believe in Darwin. Yes, the fittest virus survives. But it’s not clear what the ultimate selection parameter is.” A mutation that confers lethality, he explained, may confer another advantage scientists have not pinned down.