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Understanding viral mutation: The UK Variant

[1] Spike protein on the virion binds to ACE2, a cell-surface protein. TMPRSS2, an enzyme, helps the virion enter [2] The virion releases its RNA [3] Some RNA is translated into proteins by the cell’s machinery [4] Some of these proteins form a replication complex to make more RNA [5] Proteins and RNA are assembled into a new virion in the Golgi and [6] released. Source: Faculty of Pharmaceutical Medicine, UK.

So this is where we put all that we’ve learned about viruses over the last one year to the test, by trying to explain the UK Variant, aka VOC-202012/01 initially (denoting it was the first Variant Of Concern in December 2020) in layman’s terms.

Viruses of course are always mutating, during each replication cycle. The mutations occur within the genetic sequence contained in their RNA (SARS COV-2 is an RNA virus). Due to its loose, single line structure, RNA tends to be more prone to such mutations occurring during the replication process.

I find it useful to think of each replication cycle as sitting an exam for the virus - its task being to pull off the next copy of itself based on the information contained in its RNA (in SARS COV-2's case), while making as few errors as possible. Each mutation is essentially an error. Human cells also multiply along the same principle, but since we're DNA-based (with some RNA for non-genomic purposes), they are less prone to errors in the process thanks to the double-helix structure of DNA.

It also allows for the human genome to contain billions of base pairs that make up the genetic sequence, compared to an RNA virus that will typically be in the thousands only. SARS COV-2 is actually a bit longer than the average, containing around 30,000 base pairs.

Now each time they replicate, some of these 30,000 base pairs are copied wrongly – that is why it is said viruses are always mutating. They never get a 100% mark. But they get enough right to maintain their structural integrity and remain true to their original character. The problem starts occurring, and we need to start worrying, when many of them start making the same errors, and these errors are seen to occur along key, or biologically significant parts of the virus.

So in the case of the UK variant, it is said to contain 23 mutations. If we return to the exam analogy, we all know how a number of examinees making the same errors will set off alarm bells in the examiner’s mind that they were cheating. The more of these there are, the greater the chance that some real hanky-panky was going on. Similarly, 23 of the same mutations (errors) occurring in a single cluster (in the UK they first spotted this set of errors in 900 cases, now there’s a lot more) is an “unusually large number”.

That is what raised eyebrows in the first place. Typically, two SARS-CoV-2 viruses collected from anywhere in the world differ by an average of just 10 RNA letters (base pairs) out of 29,903, according to a UCL paper.

Not all 23 of the mutations identified in VOC-202012/01 however, are significant. Eight of the mutations occur in the Spike protein, that long protruding bit we're all familiar with by now, that the virus uses to bind itself to human cells. The Spike protein is a major target for ‘neutralizing’ antibodies that bind to the virus and render it non-infectious, and is the part of the virus against which all the vaccines have been designed. If the structure of Spike is sufficiently altered, the antibodies being activated by the vaccines may fail to recognise the enemy and do their thing.

However, among the 8 mutations in Spike in the UK variant, just 3 are said to be of particular concern. Sometimes mutations will cause what is called a ‘deletion’, which we may think of as a part of the virus identified earlier no longer being there. So that is a structural change, and 1 of these mutations along Spike is a deletion (69-70del). However from what I can understand it is not a large enough deletion yet to cause the antibodies to miss their target, which is why the doctors and vaccine makers have been saying the vaccines will still work.

The second significant mutation occurs right at the pointy end of Spike, in an area known as known as the Receptor Binding Domain, i.e. the part that the virus uses to bind to the ACE2 enzyme found on the surface of human cells, and thereby infect human beings. Most of us will have heard of ACE2 by now. It is abundant along the respiratory tract (of the most vulnerable patients at least), and that is why COVID-19 ends up damaging the lungs. There is also said to be increased expression of ACE2 in patients with diabetes, which is why they are said to be more vulnerable.

Scientists believe the mutation in the RBD (N501Y) exhibits ‘increased binding affinity to human ACE2’, which is to say it is better able to hook up with its receptor in human beings. That is why they are also saying this variant appears to be more transmissible.

The third mutation of significance is said to be so because it occurs adjacent to what is known as the Furin Cleavage Site, a property of SARS COV-2 that differentiates it from previous coronaviruses (such as SARS COV, that caused SARS) and is thought to be responsible for its high infectivity and transmissibility. But scientists also readily admit they need to study this more.

Overall, what one can gather as a lay person is that the UK variant is indeed more transmissible, but is itself neither more lethal nor evasive to vaccines/antibodies. We should be aware of what it may portend, of which the most dangerous outcome, potentially, would be more significant changes to Spike, till it actually achieves vaccine escape. And the South African variant may already have done that.

Sources: SAGE, This Week in Virology by Racaniello, et al. (Podcast)

  • Coronavirus 2 (SARS-CoV-2)
  • SARS-CoV-2
  • Covid-19
  • Coronavirus

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