A global study has unearthed a possible genetic reason why some people infected with the virus that causes COVID-19 show no symptoms.

Human leukocyte antigens – or HLAs – are important genes that support immune function in the human body, particularly in identifying viral pathogens.

And a particular variation in the HLA-B complex has been found to at least double the likelihood that a person infected with SARS-CoV-2 will be asymptomatic.

For people who inherit a copy of the HLA-B15 variant from one parent, there was a 2.4 times greater chance of avoiding symptoms. Homozygous carriers — born with copies of the variant from each parent — were 8.5 times more likely to avoid symptoms.

It’s a somewhat common variant among certain ethnicities – about 1 in 10 people with European ancestry are potential carriers – but having the gene is not a guaranteed protector against coronavirus symptoms.

The findings, published in Nature, have emerged from a joint study between researchers at the University of California San Fransisco and Australian institutions including Latrobe University, Monash University and the QIMR Berghofer Centre.

The research came about almost by accident.

Co-lead authors Professor Stephanie Gras from Latrobe and Jill Hollenbach from UCSF first met at a research conference in May 2022 and pooled their resources to track the association of possible gene variations with COVID-19 symptoms.

Their teams narrowed a group of 30,000 people with high-quality HLA data to a cohort of about 1,500 unvaccinated people who tested positive for the virus. They then focussed on five locations of interest in the HLA genes while monitoring the emergence of symptoms to determine which variants, if any, might have a greater linkage to being COVID asymptomatic.

“The [SARS-CoV-2] virus gets inside cells and ‘presents’ some small part of the virus on the surface via the HLA molecule,” Gras explains.

“Those act as a red flag for T cells. The cell sends the signal to the T cell that it has been infected with the virus, and the T cells get activated and kill that [infected] cell.

“HLA-B15 can actually present a small part of the spike protein that is very similar between SARS-CoV-2 and seasonal coronaviruses… [that] circulate every year in the population and give us the common cold during winter most of the time. They share some similarities.”

The understanding provides a possible application for future treatments. Now an association between the variant and asymptomatic cases has been identified, the Gras and Hollenbach teams have begun to study the interaction between HLA-B15 and the SARS-CoV-2 spike protein at the atomic level.

That research is already underway, including at the Australian Synchrotron at the Australian Nuclear Science and Technology Organisation.

“We’re doing atomic-level models of proteins to understand the interaction,” Gras says.

“We want to compare the T cells within people who are asymptomatic with HLA-B15 and people who are not asymptomatic with HLA-B15. Actually, HLA-B15 is not a magic bullet, you can have it and still have severe COVID.”

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