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.

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.

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.

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).

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.