Researchers at the University of California, San Francisco, have found that people who do not develop symptoms after being infected with the COVID-19 virus often carry the HLA-B*15:01 gene mutation. This genetic mutation allows people to develop a more effective immune response to the virus. The findings, from a study involving the U.S. National Marrow Donor Program, shed light on the genetic basis of asymptomatic COVID-19 and provide potential new approaches for vaccine and drug development.
Scientists have discovered a genetic variant - HLA-B*15:01 - associated with asymptomatic cases of COVID-19, opening potential avenues for new treatments and vaccines.
People who contract COVID-19 but never develop symptoms - so-called "super avoiders" - may have a genetic ace up their sleeve. They are more than twice as likely as those with symptoms to carry a specific genetic variant that helps them fight off the virus, according to a new study led by UCSF researchers.
The paper, recently published in the journal Nature, is the first to demonstrate the genetic basis of asymptomatic SARS-CoV-2. This research helps solve the mystery of why some people become infected with COVID-19 without getting sick.
The role of HLA gene variation
The secret lies in human leukocyte antigens (HLA), protein markers that signal the immune system. A mutation in a gene encoding HLA appears to help virus-killing T cells recognize SARS-CoV-2 and launch a blitzkrieg attack. The T cells of some people with the mutated gene can recognize the novel coronavirus even if they have never been exposed to it before, thanks to its similarity to seasonal cold viruses they already know. The discovery opens up new targets for drugs and vaccines.
Peptide NQK-Q8 (light color) is a spike protein of SARS-CoV-2 that the virus uses to enter cells, and it binds to the HLA-B*15:01 groove (orange). The illustration is based on the crystal structure of HLA-B*15:01 in complex with the SARS-CoV-2 viral spike-derived peptide NQKLIANQF published by Augusto et al. in 2023 (PDB entry-8ELH) (Nature). Photo credit: André Luiz Lourenço
"If you have an army that can identify the enemy early on, that's a huge advantage," explained Dr. Jill Hollenbach, the study's lead researcher and a member of UCSF's Weill Institute for Neurosciences and professor of neurology, epidemiology, and biostatistics. "It's like having soldiers who are ready for battle. They already know what to look for. They know these are the bad guys."
Prevalence and impact of HLA-B*15:01 mutations
The HLA-B*15:01 mutation is very common, with about 10% of people in the study population carrying it. It doesn't stop the virus from infecting cells, but it prevents people from experiencing any symptoms. This can include a runny nose or even a barely noticeable sore throat.
UCSF researchers found that 20% of the study population who remained asymptomatic after infection carried at least one copy of the HLA-B*15:01 variant, compared with only 9% of those who reported symptoms. People with two copies of the variant were much more likely to avoid getting sick, more than eight times as likely as carriers.
Researchers have long suspected that HLA was involved, and luckily the national registry contained the data they were looking for. The National Marrow Donor Program/BeTheMatch is the largest HLA-type volunteer donor registry in the United States, connecting donors with people in need of bone marrow transplants.
But they still need to know how well donors resist COVID-19. So they turned to a mobile app called COVID-19 Citizen Science Research developed by the University of California, San Francisco. They enrolled nearly 30,000 people who were also on the bone marrow registry and followed them during the first year of the pandemic. At the time, a vaccine was not yet available, and many people received routine COVID testing because of work requirements or in situations where they might have been exposed.
"We did not set out to study genetics, but we are pleased to see that our multidisciplinary collaboration with Dr. Hollenbach and the National Marrow Donor Program resulted in this outcome," said Mark Pletcher, MD, MPH, professor of epidemiology and biostatistics at UCSF.
Sample limitations and findings
The primary study population was limited to those who self-identified as White because there were not enough people from other ethnic and racial groups among the final study respondents for analysis.
The researchers identified 1,428 unvaccinated donors who tested positive between February 2020 and the end of April 2021, before vaccines were widely available and test results would take many days to come out.
Of those, 136 had no symptoms for at least two weeks before or after testing positive. Only one HLA variant - HLA-B*15:01 - was strongly associated with asymptomatic COVID-19 infection, and this was confirmed in two independent cohorts. Risk factors for severe COVID-19 infection, such as older age, being overweight, and having chronic medical conditions such as diabetes, do not appear to be associated with asymptomatic infection.
"We are honored to collaborate on research that has the potential to leverage long-term public investment to build a national registry to help treat disease and improve our ability to avoid future epidemics," said Martin Maiers, vice president of research at the National Marrow Donor Program/BeTheMatch.
Understanding the immune response
To understand how HLA-B15 eliminates viruses, Hollenbach's team collaborated with researchers at La Trobe University in Australia. They investigated the concept of T cell memory, or how the immune system remembers previous infections.
The researchers looked at T cells from people who carried HLA-B15 but had never been exposed to the SARS-CoV-2 virus and found that the cells still responded to a part of the new coronavirus called a peptide called NQK-Q8. They concluded that T cells in people exposed to some seasonal coronaviruses (which have a very similar peptide called NQK-A8) were able to quickly recognize the SARS-CoV-2 virus and mount a faster, more effective immune response.
Stephanie Gras, professor and laboratory director at La Trobe University, said: "By studying their immune responses, this may allow us to identify new ways to promote immune protection against SARS-CoV-2, which could be used in the development of future vaccines or drugs."