VIRUSES, LIKE all organisms, have life-cycles. Theirs are parasitic, beginning when a parent virus infects another creature and hijacks its cells to make copies of itself. In the case of SARS-CoV-2, the virus that is causing the pandemic, this happens when it latches onto an enzyme called ACE2 on the membrane of some human cells and slips its genome through into the cell. This cellular invasion is helped by a protein that studs the surface of the virus, known as the spike. Changes to the spike, driven by genetic changes from mutation, alter the virus’ overall properties, particularly its capacity to spread through populations.
The mutable nature of viruses is rooted in the randomness inherent within the process of producing copies of any object, making errors unavoidable. As host cells churn out copies of SARS-CoV-2, errors occur, called mutations. The vast majority of viruses do not survive errors in replication. But some do, and may even thrive as a result of the changes, outcompeting ancestral viruses and spreading more efficiently through their host population. There are some parts of the structure of the virus that are better able to withstand mutations: the spike protein is the most tolerant to changes. Mutated viruses which survive and thrive are called variants. These started emerging in earnest from SARS-CoV-2 in November 2020, with the emergence of the Alpha variant and its subsequent detection in Kent, in the south-east of England. New variants must hold some advantage over old ones if they are to become the dominant form of the virus. That advantage could be won in many different ways, but for a respiratory disease like covid-19, one of the most important factors is transmissibility, how easily the virus passes from one person to another.
One of the first mutations to increase transmissibility was referred to as N501Y, sometimes known as “Nelly”, one of eight mutations that characterised the spike protein of the Alpha variant. The mutation’s technical name is relatively straightforward once you understand that it is referring to changes in the virus’ genome, and this to the amino acid structure for which it encodes. The “501” means that the change is happening to the 501st amino acid in a chain of 1,273 that comprise the spike. The order and composition of these amino acids is dictated by a matching genome sequence, so that “501” refers to both the position on the genome and the position on the amino acid chain. “N” is short for asparagine, which in N501Y is swapped out for “Y”, which is tyrosine. Since different amino acids have slightly different chemical properties, this swap has an impact on the structure of the spike protein. As a result, the way electrical charge is distributed across it changes. This alters the shape of the protein slightly as areas of positive electrical charge attract areas of negative charge. Thanks to these dynamics, N501Y allows a crucial part of the spike to twist around by about 20 degrees, letting it find a more snug fit with the ACE2 receptor. Better binding occurs as a consequence, which means that any copy of the variant which enters the body is more likely to find its target and start replicating. This increases transmissibility. Other mutations perform a similar trick, freeing up different parts of the spike in different ways so that it may bind more effectively to ACE2.
Changes to the shape of spike are not the only way to increase transmissibility. Delta, the variant which was first detected in India and which is currently spreading around the world, appears to be even more transmissible than Alpha and the other variants. Quite why is not clear, as the detailed structural studies of Delta’s spike have not yet been completed. But Ravindra Gupta, a molecular virologist at Cambridge University, and his colleagues argue that Delta’s increased transmissibility is down, in part, to a mutation at site 681. This is the point on the spike where, after it has bound to ACE2, the protein is cleft in two. Dr Gupta says P681R, helped by two shape-modifying mutations elsewhere, makes it easier for the protein to be cut up and thus get into cells. Its presence also means that, once a cell starts producing particles, their spike proteins can get on to the cell’s surface pre-cut. That can lead to virus particles which are shorn of the parts which antibodies recognise and ready to fuse with any nearby cell. It can also encourage infected cells to clump together with others.
There are other theoretical mutations which make the virus more transmissible and which it has not arrived at yet (it may never do so, for they may represent contortions of the spike protein that are not physically possible). Others still help it evade the antibodies that the immune system throws at it in order to protect the body from infection—just as a spike that is shifted by a set of mutations can bind better to ACE2, so too can other shifts make it harder for antibodies to bind to spike in return. Delta is currently taking over from other variants around the world, its set of mutations letting it outcompete them in the evolutionary environment that human bodies present to it. For another variant to outcompete Delta it will need new tricks.