Structural homology of HHV-6B epitopes as candidates for molecular mimicry triggers of the onset type one diabetes mellitus

Objectives To study whether HHV-6B can act as a molecular mimic to trigger onset of Type One Diabetes Mellitus (T1DM) by assessing structural and binding similarities between HHV-6B derived epitopes and T1DM autoantigen derived epitopes. Methods Epitope peptide structures and their interactions with T1DM autoantigens were modeled using Boltz-2, a state-of-the-art artificial intelligence protein structure prediction method. Results Several HHV-6B epitopes studied here demonstrated high structural alignment with T1DM antigen epitopes, but even when structural homology was lacking, in multiple cases the HHV-6B and T1DM epitopes fit into the same binding region of the corresponding HLA molecules, suggesting a plausible structural basis for T cell cross-reactivity. These findings support the hypothesis that HHV-6B may act as a molecular mimic contributing to autoimmune responses in individuals genetically susceptible to T1DM. Conclusion This study demonstrates that structural modeling is a useful tool for identifying potential mimicry candidates that sequence-based methods may not find, underscoring the importance of integrating structure-based modeling, including docking, into molecular mimicry prediction pipelines for identifying potential epitopes for in vitro studies.