Evaluation of the effects in the <i>in vitro</i> system of synthetic thymic hexapeptide on the expression levels of NF-κB, IFNα/βR and CD119 neutrophilic granulocytes in patients with chronic herpes viral co-infections

Abstract

Background. Strategies used by herpes viruses with human cells are complex and multifaceted. On one hand, inborn defects in antiviral immune defense have been unveiled, which also affect interferon (IFN) system underlying development of chronic recalcitrant relapsing viral infections such as remittent respiratory viral infections, herpesvirus infections, and papillomavirus infections. On the other hand, numerous viruses are able to damage both immune system and IFN network. During inborn and acquired defects in IFN network, inborn or induced mutation in gene products involved in signaling cascades aimed at upregulating gene expression responsible for IFN production are observed. One of the strategies used by diverse viruses is altering some signaling pathways resulting in activated transcription factors including nuclear factor NF-kB. However, antiviral mechanisms executed by neutrophilic granulocytes (NGs), particularly affecting NF-kB expression have not been elucidated. Aim of the study: to study in vitro features of NF-kB expression and number of neutrophilic granulocytes (NG) expressing membrane IFN/R and IFNR in patients with atypical chronic active herpes virus infections (AChA-HVI), followed by assessing an effect of arginyl-alpha-aspartyl-lysyl-valyl-tyrosyl-arginine hexapeptide (HP), a synthetic analogue of the active center of the thymopoietin (active substance of drug Imunofan, Russia), on the expression of NG NF-kB and IFN/R and IFNR. Materials and methods. We observed 25 patients of both sexes aged 23 to 64 years with AChA-HVI, manifested by chronic fatigue syndrome and cognitive disorders. Study design: stage 1 clinical, ELISA, PCR methods, FC was used. Stage 2 the in vitro experiment: 32 blood samples from 8 healthy adults and 375 blood samples from 25 patients with AChA-HVI were analyzed: % NG expressing NF-kB, IFN/R, IFNR and the relevant MFI levels by using FC before and after incubation with HP. Results. Our study demonstrated low level (MFI) of NF-kB expression in 100% NG associated with decreased % of NG expressing IFN/R and IFNR in all patients with AChA-HVI and low serum level for IFN and IFN in comparison with healthy individuals. In the in vitro experiment there was shown that 100% of NG expressed NF-kB after exposure to HP. However, only 48% patients (SG 2) restored NF-kB expression level (MFI) to normal range and 52% of cases (SG 1) had no response. HP increased % of NG expressing IFN/R in SG 2 and increased % of NG expressing IFNR in SG 1. Conclusions. It was shown, that influence of HP in vitro has ambiguous effects on the expression of NF-kB, % of NG expressing IFN/R and IFNR in patients with AChA-HVI. We assume that different NF-kB response to HP is associated with inborn or secondary NF-kB deficiency.

Keywords

• herpesvirus infections
• interferon system
• nuclear factor nf-kb
• neutrophilic granulocytes
• transcription factors
• hexapeptide