Epstein-Barr Virus; A Virus That Nearly all of Us Have, Yet Few of us Know About

Next week is half term week and I will not be writing an article. Today I am writing about the most successful biological entity on planet Earth. This is the virus! This is fundamentally because of their sheer and utter abundance and complete ubiquity. Almost all pandemics, as we are now witnessing, are caused by viruses such as influenza Type A (H1NI), HIV, Ebola Virus Disease, smallpox (or variola virus) Yellow Fever, Zika or obviously COVID-19.

 

 

The Evolution of Viruses

While we, as humans, continued to evolve to become increasingly complex, viruses did exactly the opposite. Viruses simply employed a radical streamlining process and eliminated everything bar a small handful of genes. They are so efficient that COVID-19 has only 29 protein encoding genes and the influenza virus only has 14. Another group of viruses called bacteriophage have even less with only 4 genes. A virus is stripped back to the point that it is essentially a piece of inanimate complex organic matter.

It lacks any form of energy or metabolism, and cannot replicate or evolve but despite this it can still destroy us. We on the other hand have evolved to the point when we now have over 20,000 genes. Which strategy can be called the pinnacle of evolution, stripped down elegant simplicity or magnificent complexity?

Our cells are vastly more complex than even the largest virus, yet a virus can make use of our cellular physiology to compensate for its own simplicity. Viruses and humans share many common needs. Viruses even utilise and ambush our own cellular machinery so it could even be argued that they are part human. We contain all the raw materials necessary for it to replicate; all a virus does is provide the instructions. This is indeed a very elegant solution if ever the term applied.

Viruses exist in every single ecosystem on earth whether aquatic or land-based, and exploit virtually every living organism (including bacteria and plants). They are even transported in rain and tumble from the sky. Some estimates suggest there are 800 million viruses for every single square metre on the planet. What is more, the speed at which they can copy themselves and evolve will never be surpassed in nature.

This makes them extremely good at evading our immune systems and makes it very difficult for us to design vaccines. They can be both friend and foe. More often than not they are foe, but this does not diminish their significance in the natural order of things.

It is certainly true that most viruses do not have a beneficial relationship with their hosts – for us they can cause diseases ranging from a mild cold to COVID-19. Respiratory viruses are of course pernicious as they exploit our fundamental requirement to breathe. However, if viruses did not exist the world would be a very different place.

 

 

Viruses such as bacteriophages (which infect bacteria) are key in helping us control the bacterial populations in our digestive systems. Bacteriophages are widespread in nature and are major predators of the bacterial world. They help regulate bacterial populations throughout every ecosystem and without them a natural balance would be disturbed. Hence, they are essential in supporting life on earth.

In the insect world viruses in general are critical for population control and preventing species dominance. This is a natural part of any ecosystem. When populations become abundant viruses replicate rapidly. This prevents overpopulation, creates space, and prevents competitive species from flourishing to the detriment of others. This dark process called ‘kill the winner’ applies to all species including us. Hence, the pandemics that afflict humanity.

We may think COVID-19 has been terrible (0.2% mortality rate) but consider smallpox (30% mortality rate for adults or 80% in children). This virus had a reign of terror that lasted millennia. It perhaps even surpasses the bubonic plague (caused by a bacteria called Yersinia Pestis) which decimated medieval Europe.

The difference with smallpox was that it was persistent and continuous throughout the course of history. It helped lead to the decline of the Roman Empire during the Antonine Plague of 165-180 AD. It ravaged the empire’s professional armies so much that offensives were called off. It decimated the aristocracy and cut such deep swaths through the peasantry that abandoned farms and depopulated towns dotted the countryside from Egypt to Germany. It did not end there.

 

 

It annihilated the empire of the Incas in 1533 and Aztecs in 1545, who were exposed to the virus thanks to Spanish Conquistadors. Queen Elizabeth 1st contracted smallpox in 1562 and was lucky to survive but another six reigning European monarchs were not so lucky. During the 18th century it killed 400,000 Europeans each year. As recently as the 20th century it is estimated to have killed between 300 million and 500 million people.

Even in 1967, the WHO estimated that 15 million people contracted the disease and that two million died in that year. Thankfully the WHO declared the disease eradicated in December 1979. However, there is one virus which, as emerging evidence is beginning to suggest, could be added to any hot list, but few of us have heard of it. This is the Epstein-Barr virus. It may not be anywhere near as deadly as many viruses, but, as evidence suggests, it leaves us with a very different unpleasant legacy of autoimmune diseases and multiple cancers.

The Epstein-Barr Virus

The Epstein-Barr virus (EBV) is one of eight viruses in the herpes family. It is also known as human herpesvirus 4 (HHV-4). It is such a successful virus that between 90 and 95 per cent of us are infected by the time we are adults. While it is best known as the cause of glandular fever (or infectious mononucleosis), it has also been implicated with autoimmune diseases. These autoimmune conditions include SLE (or systemic lupus erythematosus), rheumatoid arthritis, multiple sclerosis, coeliac disease, Type I diabetes, inflammatory bowel disease.

It has been proven that EBV generates a protein (or antigen called EBNA2) which binds to specific regions in our DNA (or genome) that have a strong association in the expression of genes connected with these autoimmune diseases. It is also a suspected trigger for chronic fatigue syndrome (or myalgia encephalitis, ME) which possibly evolves from persistent activation of the immune system. In addition, it was the first virus to be associated with the development of cancer tumours. Since then it has also been associated with other forms of cancer.

EBV was discovered in 1964 following investigations into the cause of a disease that caused cancer in Africa. The surgeon called Dennis Burkitt who worked in Uganda at the time noticed that a particular type of cancer that affected the lymphatic system was prevalent in certain regions. He noticed it only occurred in a geographical distribution that corresponded to certain rainfall and temperature patterns. It affected 8 in every 100,000 children that lived within the areas. The effect of climate seemed to suggest that biological factors were involved.

Dennis Burkitt then sent tissue biopsies back to the UK to research staff at the Middlesex Hospital Medical School. Here Michael Epstein and Yvette Barr immediately began looking for possible cancer-causing viruses in samples of the tumours sent back from Uganda. They then identified the culprit by using an electron microscope and discovered what became known as Epstein-Barr virus. In the meantime, the disease became known as Burkitt’s Lymphoma.

Epstein-Barr virus is spread chiefly by the transfer of saliva between individuals, hence the reason why glandular fever became known as ‘kissing disease’. There are plenty of other ways to transmit EBV that are very difficult to avoid. The first time of peak EBV infection is typically between 2-4 years old. Many of us could be infected unwittingly by our mothers during childhood with little or no adverse effect. Sharing cutlery or toothbrushes or the same glass are other simple common vectors. The second period for peak EBV infection is 15 years old. At this point there is a 50% chance of contracting glandular fever.

This will result in an illness lasting a few weeks or months. Once infected with EBV it is retained for life although as a carrier it will not make you ill. Once infected the virus remain latent and hides in your immune system. Very occasionally it is possible that Epstein-Barr virus can be reactivated later in life when it can cause a wide range of conditions.

One thing we do know is that, once reactivated, the presence of the virus provides persistent stimulation to the immune system which can lead to a variety of issues such as autoimmune conditions. The difficulty with demonstrating that the Epstein-Barr virus is the main cause of these wide-ranging medical conditions we have mentioned is that almost all of us have been infected with EBV.

Association with Multiple Sclerosis

One very interesting study has just been published on January 13th, 2022, in the online journal Science. This body of work was directed at investigating the link between EBV and Multiple Sclerosis (MS). This has been the first study to provide direct evidence that EBV has a possible role in MS.

 

 

Most of us have at least an idea of what MS is. It is a disease which causes the demyelination of nerves in the central nervous system, and it currently has no known aetiology. The epidemiology regarding MS remains very unclear but EBV has been a prime suspect for some time. What we do know is that the proportion of women with MS is increasing. Roughly 2-3 women have MS for every man with the condition. In general, the people living beyond the 40o latitude north or south of the equator are far more likely to develop MS. And that is about it. Back to our study.

To determine the relationship between EBV and MS, our researchers conducted a study on 10 million young adults on active duty in the U.S. military service. Of the 10 million people 955 were eventually diagnosed with MS during their service over a 20-year period. The study took blood samples from the servicemen every 2 years to monitor their EBV status and looked at the relationship with the onset of MS. They calculated that the risk of developing MS increased 32-fold after infection by EBV but was unchanged after an infection with other viruses. Biomarkers associated with MS only increased after Epstein-Barr virus infection suggesting a strong association.

One of the lead researchers Alberto Ascherio commented, ‘the hypothesis that EBV causes MS has been investigated by our group and others for several years, but this is the first study providing compelling evidence of causality. This is a big step because it suggests that most MS cases could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for MS.’

Currently there is no way to effectively prevent or treat an EBV infection. There is a distinct possibility that an EBV vaccine or targeting the virus with Epstein-Barr virus-specific antiviral drugs could ultimately prevent or cure MS. While there is no vaccine against the Epstein-Barr virus at present, several groups are trying to develop one. On 5th January 2022, Moderna announced that it has just started a Phase 1 trial for an EBV mRNA based vaccine across the U.S. The results should be published in 2023; hopefully it will be an exciting step forward.