IMMUNE SYSTEM DISTANT EFFECTS IN PATIENTS WITH LONG-COVID ON THE BACKGROUND OF REACTIVATION HHV-6 INFECTION

Introduction. It is now known that 30% of patients who have recovered from COVID-19 develop long-COVID. According to researchers, the reactivation of herpesviruses plays a significant role in triggering long-COVID. In these patients, alteration in lymphocyte populations and T-lymphocyte subpopulations have been observed, yet the nature of these changes remains unclear. The dysregulation of the immune response caused by SARS-CoV-2 is further exacerbated by the reactivation of human herpesvirus type 6 (HHV-6). Therefore, it is essential to distinguish immune response alterations in long-COVID patients based on HHV-6 reactivation and consider these differences when developing therapeutic approaches. The aims of this study were: 1) to investigate the associative relationships between the number of lymphocyte populations, T-lymphocyte subpopulations, and the severity of the clinical course of COVID-19 in patients with long-COVID; 2) to determine and compare the percentages of CD3+, CD4+, CD56+, CD8+, CD4/25/127– T-regs and CD19+ cells in long-COVID patients depending on the presence of reactivated HHV-6. Materials and methods. In our study, we examined 124 patients, including 73 women (59%) and 51 men (41%), with an average age of 43±9.70 years, all of whom had suffered from COVID-19 in the second half of 2023. To confirm HHV-6 reactivation and form study groups, molecular genetic studies (PCR) were conducted on all patients. Subsequently, flow cytometry was used to analyze the lymphocyte populations and subpopulations in peripheral blood samples from the patients. Results. In patients with long-COVID following severe COVID-19, the percentage of CD3+ T cells, CD8+ cells, and CD4+CD25+CD127– T-regs was significantly lower both in the absence of HHV-6 reactivation (p=0.014; p=0.016; p=0.045, respectively) and during the active phase of HHV-6 reactivation (p=0.045; p=0.005; p=0.008, respectively), compared to the control group. CD4+ T cells were significantly decreased only during the active phase of the herpesvirus (p=0.045). Notably, in the active phase of HHV-6, these cells were further reduced compared to those without herpesvirus reactivation. Additionally, the number of CD19+ B cells was significantly elevated in patients with HHV-6 reactivation, compared to both the control group (p<0.0001) and patients without HHV-6 reactivation (p=0.0002). Furthermore, the percentage of CD56+ NK cells in patients with long- COVID following mild and moderate COVID-19 in the history, without HHV-6 reactivation, did not differ significantly from the control group. However, NK cells were significantly lower in patients with long-COVID after severe COVID-19 in the context of HHV-6 reactivation (p=0.0001). Conclusions. Our data confirm that HHV-6 reactivation after COVID-19 plays a role in the development of long-COVID. This is mediated through dysregulation of adaptive immune cell interactions, activation of the NF-κB signaling pathway, and increased production of antibodies with defective structure. Based on our results, patients with long- COVID following severe COVID-19, in the context of HHV-6 reactivation, may have an elevated risk of immunopathological complications, potentially including autoimmune disorders. These findings offer valuable insights for future research and potential therapeutic strategies.