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bioRxiv · 10.1101/2025.04.02.646883

Molecular Mimicry Between Epstein-Barr Virus and Human Herpesvirus-6 Proteins and Central Nervous System Proteins: Implications for T and B Cell Immunogenicity in an In Silico Study.

Almulla, A. F.·Normatov, M. G.·Supasitthumrong, T.·Maes, M.
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Abstract

BackgroundThe Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) are frequently linked to neuropsychiatric illnesses such as multiple sclerosis, depression, and chronic fatigue syndrome/myalgic encephalomyelitis. These viruses may induce autoimmune reactions by molecular mimicry, leading to damage to self-epitopes in the central nervous system (CNS). ObjectiveThis study seeks to explore the common pentapeptides present in EBV and HHV-6 viral antigens alongside various CNS-related proteins via molecular mimicry. Additionally, it will assess the immunogenicity of these shared pentapeptides in T and B cells. MethodSequence alignment was conducted to assess molecular mimicry between 32 EBV and HHV-6 antigens and 10 CNS autoantigens. Protein sequences were obtained from UniProt, structural homology was analyzed using AlphaFold and PyMol, and shared pentapeptides were identified with Alignmentaj. Immunogenicity was assessed via the Immune Epitope Database (IEDB) for potential T- and B-cell activation. ResultsA total of 91 mimicry pentapeptides were identified between viral antigens (EBV and human HHV-6), and CNS proteins. Notably, synapsin (SYN)1 exhibited the highest mimicry, sharing multiple pentapeptides with EBV nuclear antigen (EBNA)1, EBNA6, latent membrane protein (LMP)1, and early antigen diffused (EA-D) and 6 different HHV-6 antigens. Myelin proteins including myelin basic protein, myelin-associated glycoprotein, and myelin-oligodendrocyte glycoprotein also displayed shared pentapeptides with EBV/HHV-6 antigens, indicating potential immune cross-reactivity. EBNA1, EBNA2, EBNA6, LMP1, LMP2, EA-D, and BLLF1 structurally resemble CNS autoantigens and act as immunoreactive epitopes for human T and B cells. Except for EBNA2 and protein U94, all share immunogenic pentapeptide sequences with SYN1. ConclusionEBV and HHV-6 antigens mimic CNS proteins, potentially triggering autoimmune responses via T and B cell activation. Shared pentapeptides suggest a link between viral infections and CNS autoimmunity. Further research is needed to clarify molecular mechanisms and explore targeted therapies to mitigate virus-induced neuroinflammation.

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Almulla, A. F., Normatov, M. G., Supasitthumrong, T., Maes, M.. 2025-04-14. Molecular Mimicry Between Epstein-Barr Virus and Human Herpesvirus-6 Proteins and Central Nervous System Proteins: Implications for T and B Cell Immunogenicity in an In Silico Study.. https://doi.org/10.1101/2025.04.02.646883

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