Like many scientists during the Covid-19 pandemic, Jill Hollenbach was stumped by why some folks appeared to dodge the worst of the virus while others did not. But as an immunologist at the University of California, San Franciso, she had a hunch about a set of proteins called human leukocyte antigen (or HLA). These proteins dot each and every one of our body’s cells. When a virus slips inside during an infection, our cells use HLAs to display pieces of viral protein to passing immune cells, much like a waiter with a tray of cocktail drinks.
“In general, most of the studies [looking at HLA] have focused on more severe disease. Good reasons for that is that we want to figure out how to prevent people from getting very ill and understanding what underlies that,” Hollenbach tells Inverse.
But with 20 percent of those infected with SARS-CoV-2, the virus behind Covid-19, developing no symptoms at all — what’s called asymptomatic infection — it was equally crucial to parsing out this conundrum. What was it about the HLA of these individuals and, by extension, their immune systems granting invincibility against such a treacherous virus?
Researchers think it could be a genetic mutation in one type of HLA called HLA-B, helping the immune system wipe out the virus before it can do damage. In a study published Wednesday in the journal Nature, Hollenbach and her colleagues at UCSF and various research institutions across the US, UK, Brazil, and Australia, found that individuals carrying the mutation HLA-B*15:01 appeared to have pre-existing immunity to other seasonal coronaviruses and were up to eight times more likely to experience asymptomatic Covid-19.
While these findings don’t entirely explain why Covid-19 severity strikes unevenly within a population — there are other factors like age and pre-existing conditions — studies like Hollenbach’s further our understanding of the complex genetics behind Covid-19 susceptibility. They also point to ways we can beef up the immune gap, whether with vaccines or personalized medicine.
Better, faster, stronger
HLAs, also known as major histocompatibility complex molecules, are encoded in a region of the genome called the HLA complex located on chromosome six in humans. The complex is divided into three regions — HLA-A, HLA-B, and HLA-C — and there’s a lot of variability in these genes, even between family members. The variability lends to diversity in the kinds of proteins HLAs can display. Harkening back to our waiter with their tray of cocktails, this could mean differently shaped or sized trays to accommodate a particular type of drink, or in this case, viral protein.
HLAs specifically advertise their viral bits and bobs to T cells, an immune cell central to immune surveillance, infection control, and coordinating the immune responses. When a T cell sees a viral protein it recognizes, it gets activated and makes quick work of clearing the infection.
For their study, Hollenbach and her team reached out to around two million individuals from the National Marrow Donor Program, part of donating bone marrow, who had their HLA typed. (Because of the risk of rejection with bone marrow and organ transplants, HLA typing is done to match patients with compatible donors.) Nearly 30,000 people responded and agreed to be part of the study; any positive Covid-19 results and symptoms they experienced would be reported via a smartphone app that was part of UCSF’s Covid-19 Citizen Science Study.
The donors were followed over the course of a year, from April 2020 to April 2021. While Covid-19 vaccines became available in December 2020, Hollenbach and her colleagues wanted to focus on unvaccinated, infected individuals otherwise, it would have made it harder to home in on the influence of HLAs. A little over 1,420 participants were identified by the end of April 2021; the group was further whittled down to 136 individuals who had remained asymptomatic for at least two weeks after their positive Covid-19 test.
The researchers then looked at the HLA type of this group from the National Marrow Donor Program’s HLA database. Asymptomatic individuals appeared to have an HLA gene variant known as HLA-B*15:01 which, depending if you have one copy or two, conferred twice to eight times the likelihood of nary a sniffle, scratchy throat, or other symptoms if you got infected. Two other independent studies — one conducted by Sulggi Lee, an infectious disease doctor at UCSF, and another that looked at data collected from healthcare workers in the UK — also found a similar, strong association between this HLA variant and asymptomatic Covid-19.
So what was so special about this gene mutation? In a separate set of studies, where Hollenback looked at the T cell samples collected before the pandemic, some super dodgers had T cells pre-programmed to recognize and fight off seasonal coronaviruses. This meant that their immune systems already knew how to fight SARS-CoV-2, clearing the virus faster from the body than most.
Building vaccines with genetics
Since the pandemic, many genes protective against Covid-19 have emerged from the woodwork. These include a cluster of Neanderthal-inherited genes on chromosome 12 that slash one’s risk for severe Covid-19, genes associated with blood type, and, strangely enough, genes that raise the risk of developing lupus. Other studies have pinpointed genes determining whether your immune system is resilient or not, which includes susceptibility to Covid-19.
Hollenbach acknowledges the mutation her study identified is one small jigsaw in a vast genetic puzzle, explaining only why a fraction of the population may be protected. HLA-B*15:01 is a variant found among people of diverse ancestries, but most individuals involved in the study were of European descent or who self-identified as white.
“We didn’t have sufficient numbers of people with other ancestries to understand whether this particular variant is the most important in asymptomatic disease in each of those groups,” says Hollenbach. “That’s a major limitation, but we’re hoping to rectify that in the future with more analysis in other ancestries.”
She’s optimistic these findings may contribute to improving anti-viral therapeutics and preventative measures like Covid-19 and other infectious disease vaccines, especially those aiming to bolster T-cell immunity.
“This [finding] can give us some clues about how we might be able to design vaccines that take a precision medicine approach and consider a person’s HLA,” she says. “This is an opportunity to think about that and understand the immunology. We’re hopeful this will be really useful information that we and other groups can build on in the future.”
