Again and again, the new coronavirus has sloughed off small chunks of its genome, leading to changes in a viral protein that is frequently targeted by antibodies, says a new report published in nature.
- SARS-CoV-2 emerged from a yet-to-be defined animal reservoir and initiated a pandemic in 2020.
- It has acquired limited adaptions, most notably the D614G substitution in the spike (S) glycoprotein.
- Humoral immunity to S glycoprotein appears to be the strongest correlate of protection and recently approved vaccines deliver this antigen by immunization.
- Coronaviruses like SARS-CoV-2 slowly acquire substitutions due to a proofreading RNA dependent RNA polymerase (RdRp)
- Other emerging respiratory viruses have produced pandemics followed by endemic human-to-human spread.
- The latter is often contingent upon the introduction of antigenic novelty that enables reinfection of previously immune individuals.
Evolution Deleting Virus Genes
When evolution snips out a stretch of an organism’s genome, the change is called a deletion. Kevin McCarthy and Paul Duprex at the University of Pittsburgh School of Medicine in Pennsylvania and their colleagues searched a database of SARS-CoV-2 genome sequences and identified more than 1,000 viruses with deletions in the genomic region that encodes a protein called spike (K. R. McCarthy et al. Science https://doi.org/10.1126/science.abf6950; 2021). The virus uses the spike protein to invade cells.
- Further analysis showed that the deletions tended to crop up at a few distinct sites in the genomic region coding for spike.
- Some of the deletions have arisen independently multiple times, and some show evidence of spread from one person to another.
What are the deletions observed?
Whether SARS-CoV-2 S glycoprotein will evolve altered antigenicity, or specifically how it may change in response to immune pressure, remains unknown.
- We and others have reported the acquisition of deletions in the amino (N)-terminal domain (NTD) of the S glycoprotein during long-term infections of often-immunocompromised patients .
- We have identified this as an evolutionary pattern defined by recurrent deletions that alter defined antibody epitopes.
- Unlike substitutions, deletions cannot be corrected by proofreading activity and this may accelerate adaptive evolution in SARS-CoV-2.
How did they find out?
- An immunocompromised cancer patient infected with SARS-CoV-2 was unable to clear the virus and succumbed to the infection 74 days after COVID-19 diagnosis .
- Treatment included Remdesivir, dexamethasone and two infusions of convalescent serum.
- We designate the individual as Pittsburgh long-term infection 1 (PLTI1).
- We consensus sequenced and cloned S genes directly from clinical material obtained 72 days following COVID-19 diagnosis and identified two variants with deletions in the NTD.
- These data from PLTI1 and a similar report prompted us to interrogate patient metadata sequences deposited in GISAID
How did the deletions happen?
- In searching for similar viruses, we identified eight patients with deletions in the S glycoproteins of viruses sampled longitudinally over a period of weeks to months.
- For each, early time points had intact S sequences and later time points had deletions within the S gene.
- Six had deletions that were identical to, overlapping with, or adjacent to those in PLTI1.
- Deletions at a second site were present in viruses isolated from two other patients, reports on these patients have since been published.
- Viruses from all but one patient could be distinguished from one another by nucleotide differences present at both early and late time points.
- On a tree of representative contemporaneously circulating isolates they form monophyletic clades making either a second community- or nosocomially-acquired infection unlikely.
- The most parsimonious explanation is these deletions arose independently due to a common selective pressure to produce strikingly convergent outcomes
Antibody Can No Longer Identify Them
A powerful antibody against SARS-CoV-2 could not latch onto spike proteins harbouring some of the deletions that the team identified. But antibody mixtures collected from people who had recovered from COVID-19 could disable viral variants that had deletions.
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