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; a quick‑reference checklist for vaccines and immunotherapies is provided in Box 2. This ecological framing links mechanism to design across HIV/HCV/influenza/SARS‑CoV‑2 and tumor immunoediting.