1918 influenza mortalityThe 1918 influenza pandemic was particularly lethal, not only for the very young and the very old (as observed for typical influenza), but unexpectedly also for young adults, 20 to 40 years of age (pictured). It has been suggested that the increased lethality in young adults occurred because they lacked protective immunity that would be conferred by previous infection with a related virus. Reconstruction of the origins of the 1918 influenza virus provides support for this hypothesis.

Analysis of influenza virus genome sequences using a host-specific molecular clock together with seroarchaeology (analysis of stored sera for the presence of antibodies to influenza virus) indicates that the 1918 H1N1 virus arose ~1915 by reassortment of an avian influenza virus with an H1 virus that had previously emerged around 1907. The 1918 virus acquired the HA gene from the 1907 virus, and the NA gene and internal protein genes from an avian virus. This 1918 virus also infected pigs, in which descendants continue to circulate; however the human 1918 virus was displaced in 1922 by a reassortant with a distinct HA gene.

Seroarchaeology and mortality data indicate that an influenza pandemic in 1889-1893 was caused by an influenza H3N8 virus. This virus appears to have circulated until 1900, when it was replaced by a H1N8 virus (the N8 gene originating from the previously circulating H3N8 virus).

How do these events explain the unusual mortality pattern of the 1918 influenza A virus? High mortality among 20-40 year old adults might have been a consequence of their exposure to the H3N8 virus that circulated from 1889-1900. This infection provided no protection against the 1918 H1N1 virus. Protection of other age groups from lethal infection was likely a consequence of childhood exposure to N1 or H1 containing viruses (this may also have resulted in the lower than usual mortality in the elderly population). Influenza is typically highly lethal in very young children due to lack of immunologic memory.

These observations suggest that childhood exposure to influenza virus is a key predictor of virulence of a pandemic strain. Antibodies against the stalk of the HA protein protect against severe disease, but only within groups of HA subtypes (HA groups are determined by phylogenetic analysis). In 1918, antibodies against a group 2 HA subtype virus (H3) did not protect against severe disease caused by a group 1 HA subtype virus (H1). Childhood exposure might also determine mortality of seasonal influenza. For example, the high virulence of currently circulating H3N2 influenza viruses in those older than 65 years might be a consequence of infection with an H1N1 virus at a young age.

This logic can also explain mortality caused by influenza H5N1 and H7N9 viruses. Most fatalities caused by H5N1 viruses (the H5 is a group 1 HA) have been in individuals who were infected as children with an H3 virus (group 2 HA). Most fatalities caused by H7N9 viruses (group 2 HA) have occurred in individuals who were infected as children with H1N1 or H2N2 viruses (group 1 HA).

The practical consequence of this work are clearly stated by the authors:

Immunization strategies that mimic the apparently powerful lifetime protection afforded by initial childhood exposure might dramatically reduce mortality due to both seasonal and novel IAV strains.


On episode #282 of the science show This Week in Virology, the TWiV team reviews a meta-analysis of clinical trial reports on using Tamiflu for influenza, and suggestions on how to rescue US biomedical research from its systemic flaws.

You can find TWiV #282 at www.twiv.tv.

influenza-reassortmentThis week’s virology question comes from Eric, who writes:

I’m working on an MPH and in one of my classes we are currently studying the influenza virus. I’d forgotten that the genome is in 8 separate parts. Curious, I’ve been searching but can’t find any information as to why that is?

What evolutionary advantage is conferred by having a segmented genome?

Terrific question! Here is my reply:

It’s always hard to have answers to ‘why’ questions such as yours. We answer these questions from a human-centric view of what viruses ‘need’. We might not be right. But I’d guess there are at least two important advantages of having a segmented RNA genome.

Mutation is an important source of RNA virus diversity that is made possible by the error-prone nature of RNA synthesis. Viruses with segmented genome have another mechanism for generating diversity: reassortment (illustrated).

An example of the evolutionary importance of reassortment is the exchange of RNA segments between mammalian and avian influenza viruses that give rise to pandemic influenza. The 2009 H1N1 pandemic strain is a reassortant of avian, human, and swine influenza viruses.

Having a segmented genome is another way to get around the limitation that eukaryotic mRNAs can only encode one protein. Viruses with segmented RNA genomes can produce at least one protein per segment, sometimes more. There are other ways to overcome this limitation – for example by encoding a polyprotein (picornaviruses), or producing subgenomic RNAs (paramyxoviruses).

Other segmented viral genomes include those of reoviruses, arenaviruses, and bunyaviruses.

There are various ways to achieve genetic variation and gene expression, and viruses explore all aspects of this space.


On episode #281 of the science show This Week in Virology, Vincent meets up with Peter L. Salk to talk about development of the first poliovaccine, eradication of poliomyelitis, and Jonas Salk’s 100th birth anniversary.

You can find TWiV #281 at www.twiv.tv.

TWiV 280: Post viral

13 April 2014

On episode #280 of the science show This Week in Virology, the TWiVmeisters answer listener email about the NEIDL, negative results, patenting MERS-coronavirus, human papillomavirus transmission, canine distemper virus, and much, much more.

You can find TWiV #280 at www.twiv.tv.

Unraveling the NEIDL

11 April 2014

Threading the NEIDLThe NEIDL (National Emerging Infectious Diseases Laboratory) at Boston University is a newly constructed biosafety level 4 facility which can be used to study the most dangerous human pathogens. The facility is amazingly safe, as we documented in our film about the facility, Threading the NEIDL. Some members of the Boston City Council think otherwise and have moved to stop the facility from opening.

In January 2014 a draft ordinance was introduced to the Boston City Council that would prohibit BSL-4 research within the city limits. The first public hearing on the proposed ordinance is scheduled for Wednesday, April 16, 2014 at Boston City Hall. Members of the public are invited to attend and testify. I encourage you to read the proposed ordinance which is available online. If you live in the Boston area and have a view on this ordinance, you might consider attending the public hearing. The Boston City Council Calendar of Meetings should be consulted for scheduling changes.

The American Society for Microbiology has provided this statement on the ordinance:

As background information you should be aware that In 2007, the ASM filed an Amicus brief with the Supreme Court of Massachusetts on a case involving a BSL-4 laboratory affirming the importance and safety of BSL-4 research laboratories. That same year, the Society also provided similar testimony before the U.S. House of Representatives.

We believe that scientists should be aware of events that can impact science in their region and have the opportunity to voice their opinions on actions that could affect them, directly or indirectly. We urge any members who are inclined to attend.

The Boston City Council Ordinance seems ill-advised, especially since the NEIDL has gone through a supplemental risk assessment process, and has been blessed by two independent scientific groups (the National Research Council and the NIH Blue Ribbon Panel), and prevailed in Federal Court.

While it might seem frightening to have a BSL-4 facility within a major city, after having toured the NEIDL I can say with confidence that the precautions taken to prevent release of pathogens, both physical and operational, are second to none. As Elke Muhlberger noted during our tour, it is the safest place to work on Earth. I strongly recommend that the Boston City Council members view Threading the NEIDL to learn why it does not make sense to prevent opening of this facility.


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.


On episode #279 of the science show This Week in Virology, Vincent, Alan, and Kathy reveal how a retrovirus in the human genome keeps embryonic stem cells in a pluripotent state, from where they can differentiate into all cells of the body.

You can find TWiV #279 at www.twiv.tv.

Retroviruses R us

3 April 2014

HERV-HAbout eight percent of human DNA is viral – remnants of ancestral infections with retroviruses. These endogenous retroviral sequences do not produce infectious viruses, and most are considered to be junk DNA. But some of them provide important functions. The protein called syncytin, which is essential for formation of the placenta, originally came to the genome of our ancestors, and those of other mammals, via a retrovirus infection. Another amazing role of endogenous retroviruses is that they regulate the stem cells that are the precursors of all the cells in our body.

The genetic material of retroviruses is RNA, but during infection it is converted to DNA which then integrates into the chromosome of the cell.  If the infected cell happens to be a germ cell, then the viral DNA, now called called an endogenous retrovirus, becomes a permanent part of the animal and its offspring. One of our endogenous retroviruses, called HERV-H, infected human ancestors about 25 million years ago. HERV-H has been found to be important for the properties of human embryonic stem cells.

Embryonic stem cells (ES cells), which are derived from the inner cell mass of a blastocyst (which forms 4-5 days after implantation), are pluripotent – they can differentiate into every cell type in the human body. Being pluripotent means expressing a very different set of genes compared with somatic cells – the cells of skin, muscle, organs, to name a few. The genes that are expressed in ES cells are controlled by a small number of key proteins that regulate mRNA synthesis. If these proteins – just four – are produced in a differentiated cell, it will turn into an ES cell – an induced, pluripotent embryonic stem cell, or iPSC. This observation garnered Shinya Yamanaka the Nobel Prize in 2012.

The first clue that HERV-H might be important for the pluripotency of ES cells was the finding that this DNA is preferentially expressed in human ES cells (the figure [credit] shows the expression of HERV-H in ES and two other cell types). When the levels of HERV-H RNAs are reduced (by RNA interference) in ES cells, the morphology of the cells changes – they become fibroblast-like, a sign of differentiation. In contrast, when fibroblasts are reprogrammed to become iPSCs, the levels of HERV-H RNAs rise. These findings suggest that HERV-H is essential for keeping ES cells pluripotent, and for making somatic cells pluripotent.

The HERV-H DNA in our genome is flanked by viral sequences called long terminal repeats, or LTRs. These provide initiation sites for the synthesis of viral mRNAs. In human ES cells the HERV-H LTRs appear to be enhancing the transcription of nearby human genes that are important for maintaing pluripotency. In an interesting twist, the HERV-H viral RNA is important for this activity: it appears to bind proteins involved in the regulation of mRNAs important for pluripotency. This observation explains why reducing HERV-H viral RNA leads to loss of pluripotency.

The HERV-H RNA made in human ES cells is not translated into protein because it contains many mutations that have accumulated over the past 25 million years. Therefore HERV-H is a long, non-coding RNA (lncRNA), a relatively recently discovered class of regulatory RNAs. There are about 35,000 lncRNAs in human cells that are involved in controlling a variety of processes such as splicing, translation and epigenetic modifications. Now we know that endogenous retroviruses can also produce lncRNAs.

Without endogenous retroviruses, humans might not be recognizable as the Homo sapiens that today walk the Earth. They might also be egg-layers – but the eggs would be white. Viruses don’t just make us sick.


On episode #278 of the science show This Week in Virology, Vincent, Dickson, Alan, and Kathy discuss disruption of the ccr5 gene in lymphocytes of patients infected with HIV-1.

You can find TWiV #278 at www.twiv.tv.