The Link between a Common Variant in HLA Genes and Asymptomatic SARS-CoV-2 Infection

So far most global efforts have focused on severe illness in COVID-19, for example:

• The Link between TLR7 Variants and Critical COVID-19

However, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. 

Asymptomatic COVID-19

At least 20% of people who become infected with the SARS-CoV-2 coronavirus never feel sick.^[4-7] Now scientists have identified a genetic mutation (i.e.,  HLA-B*15:01) that is linked to a higher likelihood of avoiding symptoms during infection.^[1]

Here variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection was postulated.

Initially, scientists suspected that this genetic association is due to pre-existing T cell immunity.  After further study, now they show that:

The structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.

 

What is HLA genes?

Among the many genes involved in human immune responses, Human leukocyte antigens (HLA) variants have among the strongest associations with viral infections.^[2]

HLA are genes in major histocompatibility complexes (MHC) that help code for proteins that differentiate between self and non-self.

They play a significant role in disease and immune defense. They are beneficial to the immune system but can also have detrimental effects.

T Cell Cross-Reactivity

Cross-reactivity is the ability of an antigen to bind with an antibody that was raised to a different antigen. It may arise by one of two mechanisms: shared epitopes on multivalent antigens, or conformational similarity of epitopes.

In the study, scientists sought to determine whether the T cell cross-reactivity observed previously in patients with infection could be observed in unexposed individuals.  Here are their observation:^[1]

T cells from a subset of healthy donors carrying HLA-B*15:01 who were never exposed to SARS-CoV-2 were reactive to the SARS-CoV-2 peptide NQK-Q8, and most of the reactive cells displayed a memory phenotype. The sequence identity between SARS-CoV-2 and seasonal coronaviruses peptides, except for a single amino acid substitution, could explain the T cell cross-reactivity.

Seasonal Coronaviruses

Based on a Croatia study on the role of seasonal coronaviruses, rhinoviruses, adenoviruses and bocaviruses in the etiology of respiratory infections, it states that:

An overall global prevalence in respiratory tract infections was found to be between 0.5 and 18.4% for seasonal coronaviruses, between 13 and 59% for rhinoviruses, between 1 and 36% for human adenoviruses, and between 1 and 56.8% for human bocaviruses. 

Pre-Existing Immunity to SARS-CoV-2

In the study of [1],  scientists concluded that pre-existing immunity to SARS-CoV-2 is found to reflect T cell memory to circulating 'common cold' coronaviruses:  Here are their findings and conclusions:

T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses.

Finally, they have surmised that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.

References

1. A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection
2. Biochemistry, HLA Antigens
3. Seasonal Coronaviruses and Other Neglected Respiratory Viruses: A Global Perspective and a Local Snapshot
4. Meyerowitz, E. A., Richterman, A., Bogoch, I. I., Low, N. & Cevik, M. Towards an accurate and systematic characterisation of persistently asymptomatic infection with SARS-CoV-2. Lancet Infect. Dis. 21, e163–e169 (2020).
5. Oran, D. P. & Topol, E. J. Prevalence of asymptomatic SARS-CoV-2 infection. Ann. Intern. Med. 173, M20-3012 (2020).
6. Buitrago-Garcia, D. et al. Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: a living systematic review and meta-analysis. PLoS Med. 17, e1003346 (2020).
7. Ra, S. H. et al. Upper respiratory viral load in asymptomatic individuals and mildly symptomatic patients with SARS-CoV-2 infection. Thorax 76, 61–63 (2021).