An NCI-designated Comprehensive Cancer Center
By Maxine Nunes | July 28, 2020
Can a simple genetic test predict how susceptible you are to COVID-19? According to a recent study published in the Journal of Virology, the answer may be yes.
 
Using computer modeling, researchers found that genetic variations in the human leukocyte antigen (HLA) may be a key factor in your immune system response to SARS-CoV-2, the strain of coronavirus that causes COVID-19. 
 
If further research proves this study correct, then HLA typing — a simple genetic procedure — might not only help determine who is most at risk for contracting COVID-19, it may also be important in developing a vaccine that can be widely effective.
 
But what is HLA? What role does it play in the immune system? And why might one HLA type make you highly susceptible to COVID-19 while another type provides strong protection?
 
For answers, we sought out Leo Wang, M.D., Ph.D., a pediatric hematologist-oncologist at City of Hope. HLA plays an important role in his clinical work as a stem cell transplantation physician, as well as in his research, which currently involves leveraging HLA to augment chimeric antigen receptor (CAR) T cell therapy.

What is HLA?

HLA is a protein that’s part of the immune system, and each of us inherits one set of HLA genes from each parent. There are thousands of HLA types, so every individual’s HLA combination, called a haplotype, is relatively uncommon.
 
Like all proteins, HLA has a particular job to do in the body.
 
Leo Wang Leo Wang, M.D., Ph.D.
“HLA picks up degraded proteins, or peptides, in a special pocket, and brings them to the cell’s surface to show them to the immune system,” said Wang. “HLA isn’t particular. It grabs whatever will fit into its pocket — whether it’s a normal peptide or an ‘enemy’ like a virus or a cancer mutation.”
 
Each HLA type, however, can pick up only specific kinds of peptides, so one type of HLA may have a pocket into which peptides from the SARS-CoV-2 virus fit nicely, while another type might hold very few or none.
 
Distinguishing friend from foe is the job of our T cells, the immune system’s search-and-destroy team. They inspect what the HLA proteins have dredged up to the cells’ surface and decide which cells are harmless and which should be killed.
 
So if certain types of HLA can’t pick up SARS-CoV-2, the virus has a higher chance of remaining hidden and multiplying without any interference from the immune system.

HLA Typing and Its Roles in Health

The more we learn about HLA types, the more we understand about their multifaceted importance.
 
Knowing a patient’s HLA type plays a vital role in any type of medical transplant — and at City of Hope it’s necessary for anyone undergoing such procedures as bone marrow, stem cell and liver transplants.
 
“A transplant will usually include T cells from the donor. If they see the patient’s own HLA molecules as ‘foreign,’ they’ll attack and cause severe tissue damage,” Wang explained. “This is why we perform very careful HLA matching of donors and recipients.”
 
Because there are so many HLA types — and so many possible inherited combinations — the ideal donor is an identical twin, while siblings are often the next best thing. Otherwise, patients needing bone marrow transplants rely on donor databases like the National Marrow Donor Program Registry at City of Hope.
 
HLA type can also influence a predisposition to autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, sarcoidosis, lupus, celiac disease, ankylosing spondylitis and others. Thanks to HLA typing, earlier and more accurate diagnoses of such conditions are often possible, and family members who may be at risk for the same disease can also be alerted.
 
In addition, hypersensitivity to various medications such as carbamazepine, an anti-seizure drug, and abacavir, an HIV treatment, has been linked to HLA types.
 
There have also been many preliminary reports suggesting an interesting connection between HLA and cancer.
 
“HLA is associated with immunity, and with immunity comes inflammation and tissue damage, which may be associated with cancer,” said Wang. “So HLA types that predispose to inflammation might also predispose to some types of cancer.” 
 
The good news, though, is that the immune system probably eliminates the vast majority of malignant cells before they ever have the chance to turn into a tumor.

HLA Typing and COVID-19

HLA typing is a relatively simple procedure, where a cheek swab is taken and then genetically sequenced. If the study is correct, this common test may play an important role in helping us fight the virus.
 
“When you are evaluating a patient, it would be useful, of course, to know whether they had one of the HLA types that made it potentially easier for SARS-CoV-2 to hide,” Wang said — but another possibility interested him even more.
 
“If you're building a vaccine that’s going to work for everybody,” he said, “it would have to teach the T cells of patients whose HLA molecules express very little SARS-CoV-2 to recognize even the small amount they do bring to the surface.”
 
This new study may be only a first step in understanding the relationship between HLA and COVID-19 — but if it proves correct, it may be enormously helpful in understanding, and perhaps even helping end, this global pandemic.

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