HLA-A*03 may confer protection against long COVID through an enhanced immune response, 2025, Pons-Fuster et al

HLA-A*03 may confer protection against long COVID through an enhanced immune response

Eduardo Pons-Fuster, Rodrigo Martinez-Rodriguez, Lourdes Gimeno-Arias, M.J. Alcaraz, Marta Moreno, Jose M. Gómez, Ana Pelaez, Elisa García, Cristina Tomás, Angeles Muñoz, María V. Martínez-Sánchez, Inmaculada Ruiz-Lorente, Diana Ceballos, Alfredo Minguela, Enrique Bernal

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Highlights
• A significant subset of COVID-19 patients develop Long COVID.
• HLA-A*03 may play a protective role against Long COVID.
• HLA-A*03 has been shown to enhance immune responses involving CD8+ T cells and NK cells.

Background
The COVID-19 pandemic has led to widespread infection, with a significant subset of patients developing persistent symptoms known as Long COVID. Understanding the genetic factors influencing Long COVID susceptibility and severity is crucial for development of targeted interventions.

Objective
This study aimed to evaluate the impact of HLA alleles, KIR receptors, and their interactions on the development of Long COVID in patients from southeastern Spain having contracted COVID-19 during the early 2020 pandemic wave.

Methods
A cross-sectional prospective study enrolled 153 COVID-19 patients. Three months post-infection, HLA-A, –B, –C, KIR genotyping and immunological variables were analyzed using serum and blood samples. Long COVID was diagnosed three years post- infection based on persistent symptoms.

Results
Among the participants, 71 developed Long COVID.

HLA-A*03 was less frequent in Long COVID compared to non-Long COVID patients (10.7 % vs. 30.5 %, p = 0.001).

Patients with HLA-A*03 had a higher percentage of CD8+ T cells than patients with other allotypes (33.6 ± 13.4 % vs 28.7 ± 10.8 %, p = 0.033) and showed lower expression of KIR2DL1(1265 ± 547 vs 1465 ± 414 MFI, p = 0.031) and KIR3DL1 (300.6 ± 125.0 vs 398.9 ± 131.0 MFI, p = 0.047).

Moreover, NK cells in HLA-A*03 patients showed lower expression of the TIGIT inhibitory receptor (73.7 ± 12.2 % vs 78.2 ± 10.8 %, p = 0.046).

Conclusion
HLA-A*03 may play a protective role against Long COVID, potentially through enhanced immune responses involving CD8+ T cells and NK cells. Further research in larger, diverse cohorts is needed to validate these findings and to refine personalized medicine strategies for managing COVID-19 sequelae.

Link | PDF (Infectious Diseases Now) [Open Access]

 

That half of Covid patients are supposed to be LC patients probably suggests that they aren't considering a meaningful characterisation of LC, are lacking a necessary long-term follow-up (even though the patients were followed for 3 years?) or something similar, "symptom counting" isn't good enough. I might have missed it but it seems there is no stratifcation according to acute illness severity. Supposedly these patients had been infected in between Januar 2020 and March 2020 of the pandemic if I'm reading the text correctly.

 

They all seem like arbitrary criteria. In this study, there's still a symptomatic difference between groups, with one experiencing more persistent symptoms than the other. And this HLA allele is associated with these persistent symptoms. I can see it maybe being possible that they missed other associations because the group was overly heterogenous, but I don't see an issue with the association they did find.

It's also possible if they used a more strict criteria and only had ~20 people with LC instead of 71, they wouldn't have the power to find anything.

 

Have PrecisionLife said what the protective genes they think they've identified in ME/LC are? It would be so interesting if HLA-A*03 was associated with them

 

These say HLA-A*03:01 is associated with a lower risk of COVID severity and susceptibility, respectively:

Association of HLA class I genotypes with severity of coronavirus disease-19 (2021, Frontiers in Immunology)

HLA alleles associated with susceptibility and severity of the COVID-19 in Vietnamese (2024, Human Immunology)​

And these found the same allele associated with an increased immune response after COVID vaccination with the Pfizer-BioNTech vaccine:

HLA-A∗ 03: 01 is associated with increased risk of fever, chills, and stronger side effects from Pfizer-BioNTech COVID-19 vaccination (2022, Human Genetics and Genomics Advances)

Strong humoral response after Covid‐19 vaccination correlates with the common HLA allele A*03:01 and protection from breakthrough infection (2024, HLA)​

Wikipedia says the dominant form of HLA-A*03 (used in the thread paper) is HLA-A*03:01. So I think all these studies suggest that this allele is better at presenting proteins from SARS-CoV-2 - maybe specifically the spike protein which is used in the Pfizer vaccine.

 

Interesting! Thanks for digging that up!

P.s. do you mean 'presenting proteins' or 'preventing proteins'

 

Presenting.

HLA genes code for these things on almost all cells called MHC molecules. It's the job of MHC to take pieces of the proteins floating around inside the cell and "present" them on the outside, so that T cells can see what's going on inside the cell. If a killer T cell sees a cell presenting proteins that should not be in the human body, such as a COVID protein, it kills the cell, preventing the infection from spreading further from that cell.

So having HLA/MHC that is better at presenting COVID protein peptides is expected to lead to a stronger immune response since more T cells see the peptide, which should result in less severe infection and potentially more immune related side effects from a vaccine that also introduces those proteins.

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Edit: Just some more adjacent details for those curious:

There are two classes of MHC. Class I MHC presents peptides from inside the cell to killer T cells. They're found on almost all cells. They're coded by HLA-A, HLA-B, and HLA-C. That's the relevant MHC in this study.

There are also class II MHC molecules. These are found on certain immune cells called antigen presenting cells. They present peptides from proteins swimming around outside the cells to helper T cells. They're coded by HLA-D.

 

Very well explained thanks!

So is it just lowering the odds of long covid, as being vaccinated seems to? Or is it protective in some other way?

 

Well, we know higher acute severity increases LC risk, so it makes sense that a better immune response to COVID would decrease risk of LC. But this HLA allele was still associated with decreased risk of LC after they adjusted for severity, so I'm not sure.