Abstract
Recurrent infection with human alphaherpesvirus 1 (HHV-1) may be associated with immune exhaustion that impairs virus elimination. Thymic peptides enhance immune function and thus could overcome immune exhaustion. In this study, we investigated whether reactivation of herpes infections was associated with immune exhaustion. Moreover, we examined the impact of treatment with thymostimulin on the expression of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) on T and B lymphocytes in patients suffering from recurrent HHV-1 reactivation. We also assessed the effector function of peripheral blood mononuclear cells (PBMCs) after stimulation with thymic peptides. We enrolled 50 women with reactivated HHV-1 infections and healthy volunteers. We measured the expression of various activation and exhaustion markers on the surface of PBMCs using flow cytometry. In ex vivo experiments, we measured the secretion of inflammatory cytokines by PBMCs cultured with thymostimulin. Compared with controls, patients with reactivated HHV-1 infections had increased percentages of CD3+ co-expressing CD25, an activation marker (p < 0.001). Moreover, these patients had increased percentages of CD4+ and CD8+ cells co-expressing the inhibitory markers PD-1 and PD-L1. In cultures of PBMCs from the patients, thymostimulin increased the secretion of interferon gamma (p < 0.001) and interleukin (IL)-2 (p = 0.023), but not IL-4 or IL-10.Two-month thymostimulin therapy resulted in no reactivation of HHV-1 infection during this period and the reduction of PD-1 and PD-L1 expression on the surface of T and B lymphocytes (p < 0.001). In conclusion, reactivation of herpes infection is associated with immune exhaustion, which could be reversed by treatment with thymic peptides.
Highlights
Human alphaherpesvirus 1 (HHV-1) is a common pathogen; nearly 80% of people aged 22–30 years have anti-HHV-1 antibodies, and the incidence increases with age [1,2]
Jeon et al showed that CD8+ T cells close to sensory neurons latently infected with HHV-1 expressed markers of immune activation, which indicated that lymphocytes come into contact with low levels of viral antigens during latency [18].Our study found that the percentage of CD3+ and CD4+ T cells co-expressing the CD25 activation antigen was higher in patients with reactivated herpes infections than in the control group
We found that the percentages of CD8+ and CD4+ cells co-expressing PD-1 were significantly higher in patients with reactivated HHV-1 infections than in the control group
Summary
Human alphaherpesvirus 1 (HHV-1) is a common pathogen; nearly 80% of people aged 22–30 years have anti-HHV-1 antibodies, and the incidence increases with age [1,2]. Immunocompetent people combat HHV-1 infections without antiviral medications, whereas those with impaired immunity can have severe infections despite treatment [6]. Exhausted T cells display a reduced production of antiviral cytokines, decreased cytotoxicity, and an impaired immediate response to previously encountered viral antigens [7]. Cytokine Secretion in Cultures of PBMCs Stimulated with Thymic Peptides. We measured the concentrations of cytokines secreted by cultured PBMCs from 15 patients with reactivated HHV-1 infections. PBMCs were stimulated with thymostimulin (Finepharm, Jelenia Góra, Poland), which is a bovine thymic extract containing proteins and polypeptides with a mass of 4000–12,000 Da.In Poland, thymostimulin is an approved medication for patients with an impaired immune function; the impact of this substance on immune exhaustion, i.e., expression of PD-1/PD-L1 antigens, has yet to be established.Cell cultures contained 106 PBMCS/mL of medium. Cytokine concentrations in supernatants from cell cultures were measured via enzyme-linked immunosorbent assays (ELISA)
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