Interaction of Human Herpesvirus 8 Viral Interleukin-6 with Human Interleukin-6 Receptor Using In Silico Approach: The Potential Role in HHV-8 Pathogenesis

Introduction: Human Herpesvirus 8 (HHV-8) causes classical, endemic (African), and Acquired Immunodeficiency Syndrome (AIDS)-related Kaposi’s Sarcoma (KS), Body Cavity-Based Primary Effusion Lymphomas (BCBL), HHV-8-associated peritoneal Primary Effusion Lymphoma (PEL), and Multicentric Castleman’s Disease (MCD). HHV8 genome encodes several structural and non-structural proteins, among which vIL6 is a functional homologue of Interleukin-6 (IL-6). It has been established that vIL6 plays a vital role in HHV8 infections; also, it has been suggested that its function was mediated through gp130, rather than the gp80 (IL-6 receptor [IL-6R]). This study aimed to investigate the physicochemical and structural properties as well as the immunological features, and finally the interaction between vIL6 and IL6 receptor (IL6R) by using several bioinformatics tools which could provide both valuable insight into vIL6 protein and advantageous data for further studies on HHV8 inhibitors and new vaccines. Material and Methods: vIL6, human IL6 (hIL6), and IL6R were obtained from NCBI GenBank and Uniport, which were aligned by The CLC Genomics Workbench. "Signal-BLAST" and “predisi" were employed to define signal peptide; also, “Expasy’sProtParam” was used to predict physicochemical properties as well as "DiANNA", and "SCRATCH" predicted the disulfide bonds. “NetPhosK”, “DISPHOS”, “NetPhos”, ”NetNGlyc”, and ”GlycoEP” were involved to determine post-modification sites. To define immunoinformatics analysis, “BcePred”, “ABCpred”, “Bepipred”, “AlgPred”, and "VaxiJen" were used. “SOPMA”, “I-TASSER”, “GalaxyRefine”, and “3D-Refine” predicted and refined the secondary and tertiary structures. TM-align server was used to align 3D structures. In addition, docking analysis was done by “Hex 5.0.”, and finally the results were illustrated by “Discovery Studio”. Results: A signal peptide (1-22) was defined in the vIL6 sequences and analysis has shown that vIL6 is an acidic protein which is significantly stable in all organisms. Three Disulfide bonds were predicted and immunoinformatics analysis showed 5 distinct B-cell epitopes. vIL6 is predicted as a non-allergen protein and the majority of its structure consists of Alpha helix. TM-align pointed the significant similarity between vIL6 and hIL6 in protein folding. The high energy value between vIL6 protein and IL6R was calculated and further analysis illustrated 5 conserved regions as well as 4 conserved amino acids which had a significant role in vIL6 and IL6R interaction. Discussion: An in silico study by numerous software determined the possible interaction between vIL6 and IL6R and the possible role of this interaction in HHV8 pathogenesis and the progress of infection. These have been overlooked by previous studies and will be beneficial to gain a more comprehensive understanding of vIL6 function during HHV8 lifecycle and infections. Structural analysis showed the significant similarity between vIL6 and hIL6 folding which can describe the similarity of the functions or interactions of both proteins. Furthermore, several conserved regions in the interaction site which interestingly were highly conserved among all vIL6 sequences can be used as new target for vIL6 inhibitors. Moreover, our results could predict immunological properties of vIL6 which suggested the ability of this protein in induction of the humoral immune response. Such a protein may be used for further studies on therapeutic vaccine fields.