Keystone Epitope Theory in Deep Time: How Viral Endogenization and Sexual Dimorphism Wrote the Genomic Syllabus of Immunity.

Persistent infections and their antigenic “teaching sets” can dominate immune memory, but immunodominance often fails as a proxy for protection. Keystone Epitope Theory (KET) reframes this gap by treating immunity as an attention-allocation system operating in an ecological landscape of (i) long-lived “keystone organisms” that engage immunity repeatedly using relatively stable epitopes and (ii) rapidly evolving “adaptable organisms” that can deploy decoy epitopes to divert immune attention. This review extends KET into evolutionary time. We integrate evidence that “silent” sequence space is not silent (synonymous selection, codon usage, RNA-structure constraints), that host genomes are heavily shaped by viral sequence acquisition (endogenous retroviruses and other integrated viral DNA), and that perturbations such as drug hypersensitivity, critical illness, and SARS-CoV-2 infection are followed by ordered viral reactivation dynamics. We then propose non-exclusive models for why hosts retain and sometimes express endogenized viral sequences, including established mechanisms (regulatory exaptation; restriction modules; innate “viral mimicry”) and KET-motivated hypotheses (decoy detox through negative selection; immune calibration via reference epitopes). Finally, we outline experiments and multi-omic cohort designs that can discriminate among competing mechanisms and convert KET from a descriptive framework into a predictive science.