During the height of the recent COVID-19 pandemic, some people became tragically very sick whereas, around 20% of individuals had no symptoms whatsoever.


Why did some people rapidly clear the COVID-19 virus from their system?

This question has been taken up by a group of researchers at the University of California, San Francisco (USCF) through a study published in Nature: “A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection.”  (https://www.nature.com/articles/s41586-023-06331-x)

The study had a number of unexpected findings which provide important implications for the future.

Gene Mutation Fights Off the SARS-CoV-2 Virus

Along with a USCF team of scientists, immunogeneticist and lead investigator of the study Jill Hollenbach was able to identify a genetic mutation “that increases a person’s chance of being asymptomatic by nearly tenfold,” as reported by StatNews.com.  (https://www.statnews.com/2023/07/19/why-people-catch-covid-but-never-get-sick/)

“It’s just one of these natural lucky breaks,” said Hollenbach of their findings.

The HLA System

The study was based on the UCSF team’s focus on and investigation of the “variation in the human leukocyte antigen (HLA) loci which “may underly processes mediating asymptomatic infection,” as stated on the study’s abstract, with “29,947 individuals enrolled for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes.”
 
According to StatNews.com, HLA is “a molecule that helps the immune system surveil every cell of the human body and is critical during the earliest stages of infection. HLA proteins are constantly grabbing bits of chopped-up proteins they find inside or around their cells and bringing them to the surface to display them to immune cells passing by.”
 
By acting as a “biometric scanner,” immune cells are able to recognize these protein pieces as either “self” or harmless; or if HLA molecules display unrecognizable protein (such as a piece of bacterial protein or virus), the immune system will immediately produce and mobilize antibodies and T cells to attack the bacteria or virus, StatNews.com reported further. 
 

Searching the National Marrow Donor Database

However, because “HLA genes are some of the most diverse in the human genome,” with some HLA molecules “better at grabbing different kinds of proteins than others,” Hollenbach hypothesized that this variety in immune responses to SARS-CoV-2 may be caused by a particular type of HLA. 
 
To find out if her hunch was right, Hollenbach decided to explore the National Marrow Donor Program for some answers. The program has the largest database of decoded HLA genes, gathered from around 13 million individuals. HLA genes are used to find a match for people who need an organ or bone marrow transplant.
 
About 30,000 individuals were recruited from the National Marrow Donor Program registry to participate in the COVID-19 Citizen Science Study—a project that aims to “track people’s COVID exposures, infections, and symptoms” via a smartphone app. 
 
“From the time they began tracking this data until April 2021—when vaccines became widely available—more than 13,000 tested positive. Among that group, 10 percent remained completely symptom-free,” reported StatNews.com.
 

The Key Gene: HLA-B*15:01

After looking into what symptom-free individuals had in common, Hollenbach and her team discovered that “about 1 in 5 shared a common mutation”—the HLA-B*15:01 gene.
 
The discovery of this HLA gene suggested that it may be “potent” in clearing the virus that causes COVID-19. To gain a better understanding of why this is, the UCSF team gathered frozen samples of T cells that possess the HLA-B*15:01 gene that were collected long before the beginning of the pandemic.
 
After exposing the T cell samples to SARS-CoV-2, the team discovered that the T cells recognized the virus immediately. 
 
Findings from further experiments also showed that the HLA-B*15:01 gene is also efficient at seizing bits of other coronaviruses, including seasonal colds which resemble SARS-CoV-2 the most.
 
According to Hollenbach, “Individuals with this B*15:01 mutation who have these cross-reactive T cells seem to be particularly effective, very early in infection, at nuking — for lack of a better word — the virus before these folks experience any symptoms at all.” However, the team was unable to address if individuals with the HLA-B*15:01 gene are able to clear the COVID-19 virus quickly enough so as not to obtain enough viral load to be contagious.
 
That said, the human immune system is still truly remarkable!

Implications of HLA Findings

• Knowing which HLA antigen type can bind to dangerous virus proteins is tremendously important. This can be the basis for genetic therapies or other approaches to fight off infection.


• Identifying the subset of patients who do well in fighting off the SARS-CoV-2 virus is vital in controlling the spread of COVID-19 (or other viruses for that matter). If you recall, there was a huge controversy on mask-wearing. This is an example of a situation where wearing masks can prevent the spread of infection from asymptomatic individuals (who may potentially be infected with COVID-19) to others such as vulnerable myeloma patients. Awareness is KEY!
• Other categories of patients are now being studied, including those with more severe disease and are experiencing long COVID symptoms.
• There are implications for other research, such as susceptibility to developing MGUS or myeloma. The iStopMM Project’s full genetic information is available for this purpose. A focus on HLA subtypes can now be explored to closely assess if any immune category is vital in evaluating whether an individual will or will not develop MGUS or myeloma. 

The Bottom Line

This is truly a remarkable piece of investigative work by the UCSF team, revealing unknown aspects of the immune system which can help enhance our understanding, moving forward.

Several groups will be looking to confirm these findings and study the body’s key immune defenses. This is all very good news for myeloma patients and other immunocompromised individuals who have problems fighting off infections.