TWiV 426: I’m Axl, and I’ll be your cervid today

The sages of TWiV explain how chronic wasting disease of cervids could be caused by spontaneous misfolding of prion protein, and the role of the membrane protein Axl in Zika virus entry into cells.

You can find TWiV #426 at, or listen below.

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TWiV 425: All picornaviruses, all the time

The TWiVaniellos discuss a thermostable poliovirus empty capsid vaccine, and two cell genes that act as a switch between entry and clearance of picornavirus infection.

You can find TWiV #425 at, or listen below.

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TWiEVO 5: Looking at straw colored fruit bats through a straw

TWiEVOOn episode #5 of the science show This Week in Evolution, Sara Sawyer and Kartik Chandran join Nels and Vincent to talk about how the filovirus receptor NPC1 regulates Ebolavirus susceptibility in bats.

You can find TWiEVO #5 at, or you can listen below.

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TWiV 314: Einstein goes viral

On episode #314 of the science show This Week in Virology, Vincent travels to Albert Einstein College of Medicine where he speaks with Kartik, Ganjam, and Margaret about their work on Ebolavirus entry, a tumor suppressor that binds the HIV-1 integrase, and the entry of togaviruses and flaviviruses into cells.

You can find TWiV #314 at

Virology question of the week

HIV binding CD4 and ccrOn the science show This Week in Virology we receive many questions and comments, which are read every week. I also get many questions here on virology blog, which I tend to answer by email. However I think that everyone could benefit from these questions, so I’ve decided to post one here each week along with my answer.

This week’s question is from Joseph, who wrote:

I’m relatively new to virology or anything biology-related. Hell, I’m studying computer science as an undergrad at the moment; however, there’s something about virology that fascinates me – the simplistic fact that we can’t cure viruses, which are less complex than bacterium (in which we can treat, and they’ll eventually pack their bags and leave).

I’ll get to my question … since most, if not all, cells in the body replicate and reproduce and none of them merge, why do our cells let virions in? You would think after years of viral/immune system encounters, our bodies would have adapted to repelling these viruses off. I understand it’s probably much more complicated than that, but I would love to hear your answer. Does it have anything to do with virions’ size being so small?

This is a great question. In fact, I had a similar question on a midterm examination in my virology course. I phrased it this way: Could cells evolve to not have receptors for binding viruses?

I sent this answer to Joseph:

Viruses get into cells by binding to proteins on the cell surface – viruses have evolved to do this: they are safecrackers.

You would think that the cells would evolve to change these proteins – and you would be right. Over thousands of years, the cell proteins change, so the viruses can’t bind anymore.

But guess what? The viruses change right back so that they can bind to the cell protein once more.

Now you might ask: why doesn’t the cell get rid of that surface protein? The answer there is that they are needed for the cell, so they can’t be removed.

There seems to be one exception to the last statement: about 4-16% of people of Northern European descent don’t make one of the receptors for HIV. They are resistant to infection. But this doesn’t happen for most other viruses.

Joseph wrote back:

Hmm. I thought by definition virions weren’t living organisms, yet they “adapt” to bind to living cells. Sounds like those emotional virions just can’t deal with rejection – that and our cells just aren’t as smart as we need them to be. I’m not sure if you are a Trekkie; however, it reminds me of the Borg and The Enterprise’s encounter – The Enterprise adapting to The Borg’s every frequency of their phasers, bypassing their bruteforce.

That does make sense that our cells do need that protein surface for energy; however, I never thought it would actually be the surface itself. Interesting.

I did read about that somewhere – because of the Bubonic Plague causing some genetic mutation, if I’m not mistaken.

To which I responded:

Virus particles are not alive – but once they infect a living cell they can evolve.

Both cells and viruses are smart – they both have managed to be around for a long time. We have great immune systems; virus infected cells can evolve very quickly. It’s an arms race.

Correct, one idea is that the mutation conferring resistance to HIV was acquired in the Plague, but that’s hard to prove.

The mutation we are discussing is of course ccr5delta32, which confers resistance to infection with HIV-1 (the illustration shows the HIV-1 glycoprotein binding CD4 and ccr, a chemokine receptor). You can read more about ccr5delta32 here or listen to us discuss it on TWiV #278. We also talked about virus-receptor arms races on TWiV #242, and I wrote about it here.

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).

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

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

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

TWiV 46: Virus entry into cells

twiv-200Hosts: Vincent Racaniello and Dick Despommier

In episode #46 of the podcast “This Week in Virology”, Vincent and Dick continue virology 101 with a discussion of virus entry into cells, then answer reader email on colony collapse disorder and viruses that confer a benefit to their host.

Click the arrow above to play, or right-click to download TWiV #46 (35 MB .mp3, 50 minutes)

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Links for this episode:
Illustrations of virus entry into cells
Nice reference for biological items (thanks Jim!)
Colony collapse disorder: PBS program,  descriptive studymetagenomic study, genetic analysis (thanks Swiss compass!)
Potato virus Y and Alzheimer’s disease (thanks Jennifer!)
virus in a fungus in a plant (thanks Jennifer!)

Weekly Science Picks
Vincent PLoS Pearls
Dick West Nile virus website at CDC

Send your virology questions and comments (email or mp3 file) to or leave voicemail at Skype: twivpodcast

Influenza HA cleavage is required for infectivity

The influenza virus hemagglutinin (HA) is the viral protein that attaches to cell receptors. The HA also plays an important role in the release of the viral RNA into the cell, by causing fusion of viral and cellular membranes. HA must be cleaved by cellular proteases to be active as a fusion protein.

The HA on the influenza virion is a trimer: it is made up of three copies of the HA polypeptide. The cleavage site for cell proteases on the HA protein is located near the viral membrane.


In the diagram, the globular head of the HA protein, which attaches to cell receptors, is at the top, and the viral membrane is at the bottom. For clarity, only one HA cleavage site is labeled. The uncleaved form of the protein is called HA0; after cleavage by a cellular enzyme, two proteins are produced, called HA1 (blue) and HA2 (red). The two subunits remain together at the surface of the virus particle. The new amino(N)-terminal end of HA2 that is produced by cleavage contains a sequence of hydrophobic amino acids called a fusion peptide. During entry of influenza virus into cells, the fusion peptide inserts into the endosomal membrane and causes fusion of the viral and cell membranes. Consequently, the influenza viral RNAs can enter the cytoplasm. The fusion process is described in a previous post.

If the HA protein is not cleaved to form HA1 and HA2, fusion cannot occur. Therefore influenza viruses with uncleaved HA are not infectious. Cleavage of the viral HA occurs after newly synthesized virions are released from cells. Influenza viruses replicate efficiently in eggs because of the presence of a protease in allantoic fluid that can cleave HA. However, replication of many influenza virus strains in cell cultures requires addition of the appropriate protease (often trypsin) to the medium.

In humans, influenza virus replication is restricted to the respiratory tract, because that is the only location where the protease that cleaves HA is produced. However, the HA protein of highly pathogenic H5 and H7 avian influenza virus strains can be cleaved by proteases that are produced in many different tissues. As a result, these viruses can replicate in many organs of the bird, including the spleen, liver, lungs, kidneys, and brain. This property may explain the ability of avian H5N1 influenza virus strains to replicate outside of the human respiratory tract.

Like the HA proteins of highly pathogenic H5 and H7 viruses, the HA of the 1918 influenza virus strain can also be cleaved by ubiquitous cellular proteases. Consequently, the virus can replicate in cell cultures in the absence of added trypsin.

The H5 and H7 HA proteins have multiple basic amino acid residues at the HA1-HA2 cleavage site which allows cleavage by widely expressed proteases. But the 1918 H1 HA does not have this feature. Nor does the 1918 N1 help recruit proteases that cleave the HA, a mechanism that allows the A/WSN/33 influenza virus strain to multiply in cells without trypsin. An understanding of how the 1918 H1 HA protein can be cleaved by ubiquitous proteases is essential for understanding the high pathogenicity of this strain.

Chaipan, C., Kobasa, D., Bertram, S., Glowacka, I., Steffen, I., Solomon Tsegaye, T., Takeda, M., Bugge, T., Kim, S., Park, Y., Marzi, A., & Pohlmann, S. (2009). Proteolytic Activation of the 1918 Influenza Virus Hemagglutinin Journal of Virology, 83 (7), 3200-3211 DOI: 10.1128/JVI.02205-08

Viruses and the respiratory tract

Now that we have a rudimentary understanding of influenza virus replication, we can begin to consider how the virus causes disease – a field of study called viral pathogenesis. The first step in this process is virus entry into the body.

virus-entryThe human body is covered with skin, which has a dead outer layer that cannot support viral replication and also serves as a impermeable barrier. Viruses may breach the skin via a vector bite, needle injury, animal bite, or abrasion. However, layers of exposed living cells must be present to absorb food, exchange gases, and release urine and other fluids. These mucosal layers serve as easy sites of entry for viruses.

The respiratory tract is the most common route of viral entry, a consequence of the exposed mucosal surface and the resting ventilation rate of 6 liters of air per minute. The huge absorptive area of the human lung (140 square meters) also plays a role. Large numbers of foreign particles and aerosolized droplets – often containing virions – are introduced into the respiratory tract each minute. The reason why we are not more frequently infected is that there are numerous defense mechanisms to protect the respiratory tract. Mechanical barriers abound – for example, the tract is lined with a mucociliary blanket comprising ciliated cells, mucus-secreting goblet cells, and subepithelial mucus-secreting glands. Foreign particles that enter the nasal cavity or upper respiratory tract are trapped in mucus and carried to the back of the throat, where they are swallowed. If particles reach the lower respiratory tract, they may also be trapped in mucus, which is then brought up and out of the lungs by ciliary action. The lowest reaches of the respiratory tract – the aveoli – are devoid of cilia. However, these gas-exchanging sacs are endowed with macrophages, whose job it is to ingest and destroy particles.


As we discussed previously, viruses may enter the respiratory tract in aerosolized droplets produced by coughing, sneezing, or simply talking, singing, or breathing. Infection may also be spread by contact with saliva or other respiratory secretions from an infected individual. The larger aerosol droplets land in the nose, while smaller ones may venture deeper into the respiratory tract, even as far as the aveoli.

For a virus to successfully establish an infection in the respiratory tract, it must avoid being swept away by mucus or engulfed by alveolar macrophages. Then there are the more specific immune mechanisms that may intervene – a topic we’ll consider later. Suffice it to say that if a virus establishes an infection in the respiratory tract, it has surmounted a number of formidable barriers which ensure that we are not continuously infected.