As with all previous outbreaks of new virus infections, we are being warned of impending doom concerning the new coronavirus, 2019-nCoV that is now spreading globally. China’s National Health Commission Vice Minister Li Bin recently warned that ‘there is the possibility of viral mutation’. Perhaps Mr. Li is unaware that viral genomes sustain mutations during every replication cycle. More importantly, the implication of his message is that with mutation, bad things will happen. But outbreak-associated mutations do not have to increase viral replication or virulence.
As a new virus circulates in humans, mutations in the genomes occur, and some are fixed – that is, they remain as virus transmission continues. SARS-CoV, which emerged in humans in China in 2003 after transmission from open meat markets, is an example of what can be learned from the study of such changes. During the middle and late phase of the epidemic, a 29 nucleotide deletion occurred in the viral genome, in a region called Orf8, which encodes a small polypeptide. Viruses with this deletion were present in most isolates from humans during this phase of the epidemic.
It was subsequently suggested that the 29 nucleotide deletion was somehow involved in adaptation of SARS-CoV to humans. Some evidence for this hypothesis included the observation that virus replication increased in cells that over produce the protein encoded in Orf8. Furthermore, the results of some studies suggested that the Orf8 protein antagonizes the antiviral activities of interferon.
Results of a subsequent study show that the 29 nucleotide deletion decreases viral replication in a number of different cell types, including human airway epithelial cell cultures. In other words, this virus is debilitated, compared with a virus containing a full Orf8.
Normally a mutation that leads to a loss of viral fitness will disappear from the population, because viral lineages with the mutation cannot compete with more fit viruses circulating in humans. Surprisingly, during the SARS outbreak, a less fit virus remained. The authors suggest that this unusual event occurred because there was no competition – SARS-CoV had just spilled over from bats and was unique to humans. It didn’t matter that the virus was somewhat wimpy – there were no other similar viruses to outcompete it.
The 29 nucleotide deletion likely arose randomly (the deletion is not found in coronaviruses from Asian bats) and remained. It has nothing to do with adaptation to humans. In retrospect, the SARS outbreak might have been more severe had the deletion not taken place. Perhaps it is one reason why it was possible to extinguish the outbreak.
Mutations have been identified in the genomes of other zoonotic viruses, including MERS-CoV, that might also reduce virulence of the virus for humans. A single amino acid change in the ebolavirus glycoprotein has been suggested to increase replication and therefore transmission in humans. However subsequent studies showed that the change reduces virulence in animal models. It is interesting to consider that in all these cases, the selection for mutations that reduce virulence might prolong survival time of the host to allow transmission to others. Such a scenario is consistent with the fact that the strongest selection force on a viral genome is transmission to another host.
The current outbreak by a new coronavirus, 2019-nCoV, appears to have started in an open market in Wuhan, China. It seems likely that the original host was a bat, but that remains to be proven. The genome sequence of 2019-CoV shows that Orf8 is intact. If it is not lost during subsequent virus circulation in humans, the outbreak could be more severe.