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

Abstract

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-A03 was less frequent in Long COVID compared to non-Long COVID patients (10.7 % vs. 30.5 %, p = 0.001). Patients with HLA-A03 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-A03 patients showed lower expression of the TIGIT inhibitory receptor (73.7 ± 12.2 % vs 78.2 ± 10.8 %, p = 0.046). CONCLUSION: HLA-A03 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.