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The first in a new series of short articles attempting to explain the science behind fairly common topics and exploring how they relate to ME. This time we delve into the complex and somewhat controversial world of viruses - by Andrew Gladman.
Computer generated image of Rhinovirus 3 capsid comprised of hundreds of copies of 3 proteins. Within this shell there is the viral genome and several functional enzymes to allow for replication of the genome and to aid the hijacking process.
I think it safe to say that no topic is quite as disputed as the role that viruses might play in the pathology of ME. Scientists, doctors, and patients all have their own opinions about how viruses could be connected to our illness: some consider viruses to be crucial elements to our disease mechanism; others consider them irrelevant to the true causation but agree they appear to act in many cases as triggers or precipitating factors; and there are those who believe the role that viruses play has yet to be adequately determined and that the evidence remains, at best, only suggestive. But let's take a look at some of the basic concepts and consider why viruses attract so much attention in our world...
What is a virus?
A virus is generally regarded as an infectious agent, they are not thought of as living organisms as they have no means through which to reproduce by themselves, for this reason they are often classed as pseudo-living. They reproduce by invading the cells of other organisms and hijacking the cell machinery in order to produce copies of their genetic material, proteins and other structural components before assembling them into new virus particles and exiting the cell in search of new cells to hijack and further propagate themselves, this represents the sole purpose of the virus.
Video explaining how viruses infect cells and hijack the cellular machinery for viral replication.
There are millions of differing viruses in the world, with nearly every species of organism having unique viruses targeting them - there are even certain viruses that are themselves the target of viral infection! Under the broad heading of 'virus' there exist thousands of separate groups or viruses which are classified as taxonomically similar to all other organisms. Fundamentally all viruses are comprised of a strand of genetic material and a few small enzymes to replicate the viral genetic material to aid in the viral takeover of the cell, all of this is encased in a small protein shell known as a capsid. Each virus has unique additions to this basic structure but these thing are common to all viruses.
The groups thought most relevant to ME however are perhaps the enterovirus genus and the slightly more complex and controversial retrovirus. The fundamental difference between them lies in the route they take from first entering the cell to the initiation of viral protein production. Many viruses, like most organisms, use DNA (either a double or single strand) as their genetic material, this is generally integrated into the genetic material of the host cell by a protein and at this point the cell serves to unknowingly produce all the components required for viral replication. However, these two types - the enterovirus and retrovirus both use RNA as their genetic material.
BBC Secret Universe: The Hidden Life of the Cell episode exploring how viruses enter the cell, hijack it and the immune systems response to such an invasion.
Retroviruses have a single strand of RNA as their genetic material. Within their retroviral capsid there exists an enzyme known as reverse transcriptase, the function of this enzyme is to make a copy of the RNA genome in the form of DNA. This DNA then shares the same fate as the DNA in standard viruses, being integrated into the host cell genome. The important point to make here is that this enzyme is incredibly error prone. It makes mistakes very often when copying the RNA and this means that the retroviruses mutate and evolve at a much faster rate than standard viruses and are therefore much more difficult to treat due to this. This fact is the reason why HIV is so difficult to treat. The other major difference between retroviruses and standard viruses is that retroviruses have what is known as an envelope surrounding their capsid. This is a lipid membrane stolen from the host cells membrane of the cell from with the virus originates and allows retroviruses to more easily infiltrate and hijack other cells without arousing suspicion from the immune system.
Enteroviruses are also commonly discussed in ME and some researchers believe they play an important role in the pathophysiology of our disease. Interestingly however, despite the name of this genus of virus, often they only initially reproduce within the Gastrointestinal tract before migrating to other organs or tissues such as the nervous system. They also use RNA as their genetic material, however they do not use a reverse transcriptase enzyme to convert this into DNA; therefore the viral genome is never combined with the host cell's genome. Instead the RNA is replicated in the cell cytoplasm by an enzyme also injected into the cell by the virus particle known as RNA polymerase. The RNA has a molecule attached to one end which signals the cell machinery in the cell to initiate the start of protein synthesis, hence creating the viral proteins. It is unusual for enteroviruses to become chronic but researchers such as Dr. John Chia believe this to be the case in ME.
Why are viruses important in ME?
It is well documented that viruses are the most common triggering factor associated with acute onset ME - both in the form of infections and through vaccinations. It is therefore easy to understand why they have perhaps attracted most research, and yet despite this they have never been conclusively shown to be the cause of the perpetuation of ME symptoms. It appears, like most areas in ME, that research is somewhat conflicted over the extent of viral involvement.
There is some anecdotal evidence from patients and doctors who have seen improvement in health and well-being while taking or prescribing antiviral treatments such as Valcyte; however more formal research on these drugs through clinical trials has yielded something of a disappointing result. Similarly researchers such as Professor Lipkin, despite their own personal view that pathogens lie at the heart of ME, struggle to find evidence of the commonly held suspects in ME; these being viruses such as EBV, CMV and HHV6 among many others.
Attention is now turning to the possibility of a viral presence within tissue, which would allow the virus to remain undetectable by analysis of plasma and CSF samples; an example of this being the recently proposed hypothesis that viruses infected the vagus nerve. Professor Lipkin also is keen to explore the gut microbiome as this could be another location where viruses or pathogens may be lurking and adversely effecting the gut micobiota.
As time goes on it appears that research into the association of viruses and ME is evolving and moving away from the idea that viruses are the sole causative agent. Now we are seeing increasing efforts to look more at their role in either acting as a triggering mechanism, a co-morbid problem or perhaps acting as a source of dysregulation in other areas such as the gut microbiome. One can hardly discuss viruses and ME without giving a fleeting mention to XMRV. Heralded for some time as the sole agent at the heart of the disease, the story of XMRV acts as something of a fitting metaphor for the history and state of viruses and their relation to our disease as a whole. Whilst considered at the time as a momentous breakthrough, XMRV lost it's momentum over time as the evidence to support the hypothesis became dwarfed by the evidence against it.
Perhaps the idea of viruses as the cause of ME became so popular because it gave a simple explanation for a complex disease, but so often it is the simple explanations that are the wrong ones in medicine - with complex diseases requiring devious explanations. Certainly for some, viruses may be still be considered the true causative factor, but as time goes by and the research mounts, viruses seem to be something of a sirens song - promising answers but delivering little in return for the effort put in.
If anyone has any requests or suggestions of topics for future installments be sure to let me know in the comments below.
Next time we delve into the up and coming hypothesis for ME - the complex topic of autoimmunity.
Further videos:
Video exploring how the genetic material of viruses itself can be recreated artificially (viriods)
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