Keystone Epitope Theory: An Ecological Perspective on RNA Viruses, Tumor Immunoediting, and Vaccine Design

Keystone Epitope Theory proposes that persistent, human-adapted DNA viruses focus postnatal immunity on conserved, function-linked epitopes and coordinate T-, B-, and NK-cell programs within tissue niches. Here we read fast-evolving RNA viruses and tumors through that lens. RNA viruses succeed by inflating mutable decoys and engineering peptide–HLA display so cytotoxic T-cell visibility falls while inhibitory NK tone is preserved; tumors converge on the same interoperability fault lines. We formalize “decoy versus constrained” grammar, map display engineering (e.g., HLA-E/NKG2A; HIV Nef/Vpu), and outline design rules: target epitopes with measurable fitness cost, avoid decoys that reinforce inhibitory checkpoints, and normalize display so wins are visible to both CTL and NK arms. A one-page primer with pointers to mechanistic background is provided in Box 1. This ecological framing links mechanism to design across HIV/HCV/influenza/SARS-CoV-2 and tumor immunoediting.